Epidemiology of Melanoma in the Czech Republic in East Bohemia in the Period 2002–2017 and the Effect of the Annual Sunshine Exposure

A B S T R AC T Aim: The evaluation of the trend in the occurrence of melanoma nodulare, melanoma superficiale, lentigo maligna and melanoma in situ in the period of 2002–2017 in East Bohemia region in the Czech Republic. We examine if the annual numbers of hours of sunshine could affect the number of patients with melanoma. Method: In the peridod of 2002–2017, altogether 2230 patients with new diagnosis of melanoma were examined. We studied 1) If there is some trend in the occurrence of lentigo maligna and melanoma in situ, melanoma superficiale, and melanoma nodulare and if there is a difference in the age of patients with this diagnosis (adjusted calculation of specific kind of melanomas and adjusted calculation of age). 2) If the annual numbers of hours of sunshine affect the trend in the occurrence of melanoma and if the annual numbers of hours of sunshine affect the body site of melanoma. Results and conclusion: Our study confirmed that the number of patients with lentigo maligna and melanoma in situ had increased in East Bohemia region in the period of 2002–2017. The number of melanomas of nodular and superficial type does not increase. The total number of melanomas in this period does not increase either. No difference of the age of patients with melanoma nodulare, superficiale, lentigo maligna and melanoma in situ was confirmed. We confirmed no relation of the annual numbers of hours of sunshine to the number of melanoma and to the body site of melanoma.


INTRODUCTION
There is a universal agreement that the incidence of mel anoma diagnoses increases and a similar trend has been observed in Europe, but the higher melanoma incidence has not been fully explained (1)(2)(3)(4)(5). Multiple studies using the US Surveillance, Epidemiology and End Results (SEER) Program and National Program of Cancer Registries have consistently reported increasing melanoma incidence be tween 1973 and 1997 (6)(7)(8). More recent studies (1992)(1993)(1994)(1995)(1996)(1997)(1998)(1999)(2000)(2001)(2002)(2003)(2004)(2005)(2006) reported that melanoma incidence increased by 3% to 4% per year across most demographic groups (1,9). Melanoma arises through multiple different causal pathways and re flects a dynamic interdependence between environmental factors and genetic alterations. Several factors have been identified that significantly influence the incidence and the clinical and oncogenic characteristics of this disease. These factors mainly comprise increased UV exposure, tanning bed use, family and personal history of melanoma, and cer tain phenotypical characteristics, such as fair skin and hair color. Epidemiological data support two major pathways in the pathogenesis of cutaneous melanoma: one by cumula tive sun exposure to the site of the future melanoma in sun sensitive people and other by early sun exposure and nevus proneness, promoted by host factors, intermittent sun ex posure, or both (11)(12)(13)(14)(15)(16)(17)(18).

THE AIM OF THIS STUDY IS TO EVALUATE:
1) If there is some change in the occurrence of lentigo maligna, melanoma in situ, melanoma superficiale and melanoma nodulare from the year 2002 to the year 2017 (the incidence) and if there is some change in age of melanoma diagnosis. 2) If the annual numbers of hours of sunshine could affect the number of patients suffering from melanoma nodulare, superficiale, lentigo maligna and melanoma in situ. 3) If there is some relation between the annual numbers of hours of sunshine and the body site of melanoma (lentigo maligna, melanoma in situ, melanoma super ficiale and melanoma nodulare). . The data about annual number of hours of sunshine were obtained from the Hydro -metereological Institute in Hradec Králové. To analyse the data we used the multiple regression mod el. We also included the number of hours from the pre vious two years as a lag variable because it could effect the formation of melanoma in the following year. The age distribution changes year after year. This is the reason why we have to use standardization to be able to compare the number of patients in various years. We used the year 2017 as a standard. In each year we formed age groups five years wide, that is, 0-4, 5-9, 10-14, etc. In each year we counted the number of patients with a cer tain type of melanoma for each group and divided it by the number of inhabitants in that group in the given year. That gave us the agespecific incidence. When we multi plied it by the number of inhabitants in the age group in the standard year, we obtained what we called an adjusted number of patients in the age group for the given year. We added the adjusted numbers over all the age groups in the given year to obtain an adjusted number of patients in that year.

PATIENTS AND METHODS
To calculate the average age of patients in a given year, we followed the idea that is used when we calculate the mean when only a histogram is presented. We took the midpoint of each group in a given year, multiplied it by the adjusted number of patients in the group and summed the products up over all the groups in the given year. When the sum of products obtained in this manner was divided by the adjusted number of patients in that year, it gave us the adjusted average age in that year.
Unfortunately, major administrative changes were made as to the division of the country into smaller re gions during the year 2001. These changes made the dis tributions of ages incomparable and intractable. This was the reason why we could make adjustment to numbers of patients and calculations of adjusted ages only beginning with the year 2002. Since the year 2017 was the last one in which the patients' data were recorded, sixteen years of adjusted numbers and ages of patients were available.

RESULTS
In the period 2002-2017, altogether 2230 patients with new diagnosis of melanoma were examined, 1102 men (49.4%) and 1128 women (51.6%). The cases of mucosal, desmoplastic melanoma and melanoma of unknown ori gin are also included in the whole number of melanomas examined in this period. The total number of patients (men, women) with new diagnosis of melanoma in every year of this period is shown in Table 1.
The statistical evaluation of the trend in the occurrence of new melanoma (total number of all kinds of mela nomas) and the age of the diagnosis in the period of 2002-2017 was performed (adjusted number of patients with mela noma and adjusted average age of diagnosis) - Table 2. The difference in the occurrence of the total number of mela noma in the period 2002-2017 was not confirmed -Graph to Table 2. The change in age of melanoma diagnosis was not confirmed either. Regarding the histology, lentigo ma ligna and melanoma in situ was confirmed in 441 patients, melanoma nodulare in 388 patients and melanoma super ficiale in 1404 patients, 55 of them suffered from multiple melanomas.
1) The evaluation, if there is some change in the occur rence of lentigo maligna, melanoma in situ, melanoma superficiale, and melanoma nodulare from the year 2002 to the year 2017 and if there is some change in age of di agnosis.
We studied the dependence of the adjusted number of patients on the year of the first occurrence/diagnosis. The statistical evaluation of the difference of the occur rence of melanoma nodulare, superficiale, lentigo malig  Graph to Table 2 The  Table 3, Graph to Table 3.
The statistical evaluation of the change in the age of the di agnosis in patients with melanoma nodulare, superficiale, lentigo maligna and melanoma in situ (adjusted average age of diagnosis) was performed. The difference in the age of patients with melanoma nodulare, superficiale, lentigo maligna and melanoma in situ in the period of 2002-2017 was not confirmed - Table 4, Graph to Table 4.
2) The evaluation if the annual numbers of hours of sunshine could affect the number of patients suffering from melanoma nodulare, superficiale, lentigo maligna and melanoma in situ.
Graph to Table 3 The trend in the occurrence of melanoma nodulare, superficiale, lentigo maligna and melanoma in situ in period 2002-2017 was performed (adjusted number of patients with melanoma nodulare, superficiale, lentigo maligna and melanoma in situ), (axis x -year, axis y -the adjusted number of patients with specific kind of melanoma, blue -lentigo maligna a and melanoma in situ, black -melanoma superficiale, red -melanoma nodulare).   Graph to  It turns out that the number of patients was independ ent of the number of hours of sunshine. All the p-values regarding the regression coefficients associated with the number of hours of sunshine were greater than 0.05 indi cating the acceptance of the null hypothesis that these co efficients are zero which means independence. The length of sunshine in hours in every year in the period 2002-2017 and the total number of melanomas, number of melanoma nodulare, superficiale, lentigo maligna and melanoma in situ is shown in Table 5.
3) The evaluation if there is some relation between the annual numbers of hours of sunshine and the body site of melanoma (lentigo maligna, melanoma in situ, melanoma superficiale, and melanoma nodulare. We also examined the effect of the number of hours of sunshine per year on numbers of melanoma with various locations on the body. Upper, lower limbs, and face were put together as they form a location exposed to sun. We used a regression model to determine whether there is any dependence of the number of melanomas on hours of sunshine. The relation between the number of mel anomas (lentigo maligna, melanoma in situ, melanoma nodulare, melanoma superficiale) in body site exposed to sun (face, upper limbs, lower limbs) and the annual length of sunshine in hours is shown in Table 6. In all the cases the p-values were larger than 0.05, which means no dependence was confirmed. The relation between num ber of melanomas on face (lentigo maligna, melanoma in situ, melanoma nodulare, melanoma superficiale) and the annual length of sunshine in hours was not confirmed either - Table 7. In all the cases the p-values were larger than 0.05, which means no dependence.We also included the number of hours from the previous one year and two years as a lag variable because it could affect the formation of melanoma in the following years -the relation was not confirmed either.

DISCUSSION
According to the literature, the incidence of melanoma steadily increases in both sexes and further improvement in primary prevention and early detection strategies is crucial (19). Yet the epidemiologic, genomic, and anatomic profiles of the disease significantly differ across the world and mostly depend on a constellation of environmen tal and (epi) genetic factors. In this study, we evaluated the changes in epidemiology of melanoma in the period from the year 2002 to the year 2017 in Eastern Bohemia region in the Czech Republic in central Europe. There are 551 thausand inhabitants in the region and its area is 4759 square km. The advantage of our study is that all patients included in this study were personaly examined and were followed up at the Department of Dermatolo gy, Faculty Hospital Hradec Králové, Charles University, Czech Republic. We studied the dependence of the adjust ed number of patients on the year of the first occurrence/ diagnosis. The statistically important changes in the oc currence of melanoma nodulare and superficiale were not confirmed, but the increase in the occurrence lentigo Tab. 5 The annual length of the sunshine in hours in the period 2002-2017 and the number of melanomas. The relation between total number of melanomas, lentigo maligna, melanoma in situ, melanoma nodulare, melanoma superficiale and annual length of sunshine in hours was not confirmed. We also included the number of hours from the previous one year* and two years* as a lag variable because it could effect the formation of melanoma in the following years -the relation was not confirmed. Tab. 6 The relation between number of melanomas (lentigo maligna, melanoma in situ, melanoma nodulare, melanoma superficiale) in body site exposed to sun (face, upper limbs, lower limbs) and the annual the length of sunshine in hours was not confirmed. We also included the number of hours from the previous one year* and two years as a lag variable because it could effect the formation of melanoma in the following years -the relation was not confirmed.

Adjusted number of melanomas
Year Annual sunshine hours Lentigo maligna, melanoma in situ exposed Melanoma nodulare exposed Melanoma The relation between number of melanomas on the face (lentigo maligna, melanoma in situ, melanoma nodulare, melanoma superficiale) and the annual length of sunshine in hours was not confirmed. We also included the number of hours from the previous one year* and two years as a lag variable because it could effect the formation of melanoma in the following years -the relation was not confirmed. maligna and melanoma in situ in the period 2002-2017 was confirmed. We would like to make a comment on the fact, that it is not true, that the number of melanomas of nodular and superficial type increases. The total number of melanomas according to the adjusted calculation does not increase either. Nor did we confirm the difference in age of melanoma diagnosis (melanoma superficiale, mel anoma nodulare, lentigo maligna and malenoma in situ)the age of melanoma diagnosis is approximately 60 years. Also, we did not confirme the differnece of the occurrence of melanoma between men and women. These results are in contrast to other studies. Data on melanoma from the majority of countries show a rapid increase of the inci dence of this type of cancer with a slowing of the rate of incidence in the period of 1990-2000. Males are approx imately 1.5 times more likely to develop a melanoma than females while, according to other studies, the different prevalence in both sexes must be analyzed in relation to age: the incidence rate of melanoma is grater in women than in men until they reach the age of 40 years, however, by 75 years of age, the incidence is almost 3times as high in men versus women (20). On the other hand, a recent study of the Centers for Disease Control and Prevention database suggests that incidence in New England states may be decreasing (10). At this study, melanoma death and incidence rates per state during 2003 and 2013 were re corded. Rates were per 100 000 persons and were agead justed to the 2000 standard population of the US Census Bureau's population projections series (10). Additional factors may have contributed to the observed increased melanoma incidence. Melanoma in situ (stage 0) lesions represent an increasingly larger percentage of the overall increase in melanoma incidence. For example, while there have been on average 2.6% annual increases in all US mel anoma diagnoses in recent years, melanoma in situ diag noses increased at an annual rate of 9.5%. Similar trends have been noted in Europe and Australia (21,22). These results are in agreement with the results of our study. The increased proportion of earlystage lesions suggests that factors related to overdiagnosis, screening, an increased number of biopsy specimens, and incomplete report ing may have contributed to the increased incidence of melanoma. One explanation for increased melanoma in cidence with stable mortality is the misclassification by pathologists of biologically benign melanocytic lesions as melanoma. Although the histologic criteria for mela noma have been welldefined, it is not possible to predict the biologic behavior of lesions that share features over lapping with nevi and melanoma (23)(24)(25)(26). On the other hand, it has been suggested that the melanoma "epidemic" is primarily the result of previous underdiagnosis rath er than current overdiagnosis, resulting from improved histologic diagnostic criteria that allow melanomas to be recognized more accurately and at earlier stages (27). There is also an important role of screening and increased biopsies. Skin cancer screenings sponsored by the Amer ican Academy of Dermatology began in 1985 and since that time increased melanoma awareness has resulted in an increasing fraction of the population being screened for melanoma (28,29). Several studies have documented a correlation of increasing melanoma incidence with bi opsy (30). Although the majority of increased melanoma diagnoses are represented by thin lesions, diagnosis of thicker lesions has also increased over the past decades (31). Melanoma incidence has increased without regard to socioeconomic status, which is a surrogate marker for access to care and screening, (32). We evaluated also the relation between the length of sunshine in hours in every year in the period 2002-2017 and the total number of melanomas. It turns out that the number of patients was independent of the number of hours of sunshine. We also examined the effect of the number of hours of sunshine per year on numbers of mel anoma with various locations on the body. The relation be tween the number of melanomas (lentigo maligna, mela noma in situ, melanoma nodulare, melanoma superficiale) in body site exposed to sun (face, upper limbs and lower limbs) and annual length of sunshine in hours was not confirmed. We also included the number of hours from the previous one year and two years as a lag variable because it could effect the formation of melanoma in the follow ing years -the effect was not confirmed. According to the literature, there is a strong evidence that an intermittent pattern of sun exposure increases melanoma risk. Chron ic sun exposure shows no association, or a weak inverse association with melanoma risk. Total lifetime sun expo sure is positively associated with melanoma risk, but the relationship is weaker than that for intermittent sun ex posure. Sunburn is a marker of an intermittent pattern of sun exposure and there is a tendency for greater consist ency of positive associations for sunburn than for inter mittent exposure; significantly higher risk was found for intermittent than chronic exposure among studies that published results for both exposures (33)(34)(35)(36)(37)(38)(39)(40)(41)(42).The role of ultraviolet radiation exposure as a leading environmental cause of melanoma is supported by a wealth of descriptive evidence in the past, including a high prevalence of mel anoma in populations that migrated from a low to a high ambient ultraviolet radiation environment, a higher inci dence in fair skinned compared with darker skinned indi viduals and a latitude dependent rise in melanoma rates among white populations with proximity to the equator (43,44). However, differences in rates between indoor and outdoor workers and variations in the anatomical distri bution of the tumour suggest a complex association of melanoma with ultraviolet radiation that does not confirm a straightforward dose relationship model. A history of in termittent exposure to excess ultraviolet radiation doses and of painful sunburns, as a marker of host sensitivity, were a consistent finding in the majority of case-control studies and were confirmed in recent systematic reviews (42,45).
According to the study by Swerdlow, the incidence of malignant melanoma of the skin has risen rapidly in Eng land and Wales, especially in women. Mean incidences in the 14 English health regions and Wales correlated nega tively with latitude and positively with hours of sunshine, suggesting that exposure to sunshine was an important causal factor. Male and female incidences within a re gion tended to show similar yearly fluctuations, implying a common factor affecting the incidence in both men and women with a short latent period of action. This factor may be exposure to sunshine, which may cause melanoma after an induction period of about two years; for women the incidence of melanoma in the regions of England and Wales correlated positively with hours of sunshine two years earlier (46).

CONCLUSION
The number of patients with lentigo maligna and melano ma in situ increased. The number of melanomas of nod ular and superficial type does not increase and the total number of melanomas does not increase either. No dif ference of the age in patients with melanoma nodulare, superficiale, lentigo maligna and melanoma in situ was confirmed. No relation of the annual numbers of hours of sunshine to the number of patients with new diagnosis of melanoma and to the body site of melanoma was con firmed either.