Melanoma Incidence in Czech Republic, the Relation between Histology, Body Site of Melanoma, and Duration of Lesions

A B S T R AC T Aim: To evaluate the occurrence of melanoma in the period 1996–2017 in East Bohemia region in the Czech Republic. Method: We studied the incidence of melanoma and the age of diagnosis (adjusted calculation) and the parameters such as histology, body site of lesions, the length of the duration of lesions in 2810 patients. Results and conclusion: No change in the occurrence of melanoma and in age of melanoma during this period was found. The difference between men and women was not confirmed in histology, but the difference between men and women was confirmed in the body site of lesion and in the length of duration of lesion. No relation between the length of duration of lesions from which melanoma had originated and its histology was confirmed. The relation was confirmed between histology and body site of melanoma. The relation between the body site and the length of duration of previous lesions was confirmed also. The increasing occurrence of melanoma on the trunk according to the duration of the previous lesions was confirmed.


KEY POINTS
Question: What is the incidence of melanoma and is there any relation between the histology of melanoma, body site of melanoma, and the duration of lesion?
Findings: 2810 patients with a new diagnosis of mela noma were examined in the period of 1996-2017. The change in the occurrence of new melanoma and the age of melanoma was not confirmed. The relations between the followed parameters are shown in the study.
Meanings: The increase in the occurrence of melano ma on the trunk according to the duration of the previ ous lesions was confirmed; women suffer significantly more often from melanoma on lower limbs and on upper limbs, men suffer significantly more from melanoma on the trunk.

INTRODUCTION
Melanoma is one of the most malignant skin tumors with constantly rising incidence worldwide, especially in fair skinned populations (1)(2)(3). Historically, melanoma was a rare cancer, but in the last 50 years its incidence has risen faster than almost any other cancer. Skin cancer (the majority attributed to melanoma) was the cause of almost 2000 deaths in Australia in 2010 and it is current ly the most common cancer in young Australians aged 15 to 39 years (4)(5)(6)(7). In the United States alone, 87,110 indi viduals were predicted to be diagnosed with melanoma in 2017 (2,5). If melanoma is diagnosed in its early stages, resection of the lesion is associated with favourable sur vival rates (3,8). Once melanoma is advanced, surgery is no longer sufficient and the disease becomes more difficult to treat (3,(8)(9)(10). However, more recently developed im munotherapeutic treatments combined with radiation can improve survival further to several years (9).
As the incidence of melanoma steadily increases in both sexes, further improvement in primary prevention and early detection strategies is crucial (11). Melanoma arises through multiple various causal pathways and re flects a dynamic interdependence between environmental factors and genetic alterations. Epidemiological data sup port two major pathways in the pathogenesis of cutane ous melanoma: one by cumulative 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 exposure, or both (12)(13)(14)(15)(16)(17)(18). 5) The relation between the length of the duration of le sion and the body site of melanoma. 6) The relation between the histology and the length of the duration of lesions from which the melanoma had arisen.

STATISTICAL ANALYSIS
We evaluated 1) The occurrence of new melanoma in years 1996-2017 in men and in women 2) If there is some change in the occurrence of new melanoma (the incidence) from the year 2002 to the year 2017 and if there is some differ ence in age of diagnosis.
The age distribution changes year after year. This aging of the society is caused mainly by the post war baby boom repeated one generation later. This is the reason why we have to use standardization to be able to compare the num ber 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 certain 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 multiplied 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.
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 regions during the year 2001. These changes made the distributions 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. Regarding the evaluation of the relation between other parameters (his tology of melanoma and body site of melanoma; histology of melanoma and the length of the duration of lesion; body site of melanoma and duration of lesions), we included the patients from the period 1996-2012. Pairs of these classifi cations were entered in the contingency tables and the chi square test for independence of these classifications was perfomed with the level of significance set to 1%.
The statistical difference between men and women was not confirmed (p-value = 0.887). DIFFERENCE IN THE  OCCURRENCE OF NEW MELANOMA FROM  THE YEAR 2002 TO THE YEAR 2017 AND IF THERE  IS SOME DIFFERENCE IN AGE OF DIAGNOSIS  (THE INCIDENCE). We studied, if there is an increase in the occurrence of new melanomas and if there is some difference in age of mel anoma diagnosis from the year 2002 to the year 2017. The calculations were done with respect to the number of in habitants in the region and to average age of inhabitants in this region (the adjusted calculation). The statistical evaluation of the difference of the occurrence of new mel anoma and the age of the diagnosis in period 2002-2017 was performed; it is shown in the Supplement to Table 1.

2) IF THERE IS SOME
The difference in the occurrence of melanoma in the peri od 2002-2017 was not confirmed. The statistical difference in age of melanoma diagnosis was not confirmed either. p-value 0.000* lesions in the duration of 0-4 years appear on the trunk in 33.6%, in the duration of 5-9 years in 41.3%, in the dura tion over 9 years in 44.5%, and since childhood in 50.7%.

6) THE RELATION BETWEEN THE HISTOLOGY AND THE LENGTH OF THE DURATION OF LESION FROM WHICH THE MELANOMA HAD ARISEN.
We evaluated the relation between the duration of lesions (0-4 years, 5-9 years, 10-19 years, over 19 years, since childhood) and the histology (lentigo maligna, melanoma in situ, nodular melanoma, superficial melanoma). From lesions in the duration of 0-4 years, lentigo maligna was confirmed in 7.8%, melanoma in situ in 9.8%, melanoma nodulare in 17% , and melanoma superficiale in 65.4%. From lesions in the duration of 5-9 years, lentigo maligna was confirmed in 8.3%, melanoma in situ in 11.7%, melanoma nodulare in 11.2% and melanoma superficiale in 68.8%. From lesions in the duration of 10-19 years, lentigo malig na was confirmed in 7.4%, melanoma in situ in 13.2%, mel anoma nodulare in 11.9%, and melanoma superficiale in 67.5%. From lesions in the duration over 19 years, lentigo maligna was confirmed in 11.1%, melanoma in situ in 9.5%, melanoma nodulare in 15.9%, and melanoma superficiale in 63.5%. From pigmented nevus since childhood, lentigo maligna was confirmed in 8.1%, melanoma in situ in 8.9%, melanoma nodulare in 15.2%, and melanoma superficiale in 67.8%. The relation between the duration of lesions and his tology was not confirmed (p-value = 0.390). The total num ber of patients was 2271. The relation is shown in Table 7.

DISCUSSION
There have been many interesting papers regarding the epidemiology and incidence of melanoma to come out in recent years. According to the literature, further work is needed to understand fully the issues raised by several studies (20). In this study, we evaluated as the incidence both several parameters in epidemiology of melanoma in the period from the year 1996 to the year 2017 in East Bohe mia region in the Czech Republic in middle Europe. There are 551 thousands inhabitants and the area of this region is 4,759 square km. The advantage of our study is that all patients includ ed in this study were personaly examined and were fol lowed at the Department of Dermatology, Faculty Hospi tal Hradec Králové, Charles University, Czech Republic. According to the adjusted calculation, we did not confirm the statistical important difference in the occurrence of new melanomas in the period from 2002 to 2017, neither between men and women; nor did we confirm the differ ence in age of melanoma diagnosis -the age of melanoma diagnosis is 59-62 years in this period. Also, we did not confirmed the difference in the occurrence of lentigo ma ligna, melanoma in situ, melanoma superficiale, and mel anoma nodulare between men and women. On the other hand, we confirmed the statistical difference between men and women in the body site of melanoma and the length of the duration of lesions. Our study shows that women suffer significantly more often from melanoma on low er limbs (31.8% women, 11.5% men) and on upper limbs (21.2% women, 15.9% men). On the other hand, men suf fer significantly more from melanoma on the trunk (58% of men versus 31.6% of women). The duration of lesion of 0-4 years was confirmed in 54.5% of women but only in 46.5% of men.
We also evaluated the relation between the parame ters, such as the histology, the length of the duration of lesion from which the melanoma had arisen, and the body site of melanoma. We confirmed that there is a significant relation of body site of melanoma to its histology and to the length of the duration of lesions which melanoma had arisen from. No relation was confirmed between the length of the duration of lesions and its histology. Our study shows that lentigo maligna, melanoma in situ, mel anoma nodulare, and melanoma superficiale are found from 45.2% to 47.6% on a trunk but lentigo maligna is found more often on a face (29.3%) and less often on lower limbs (9.6%), melanoma in situ only in 7.2% on a face but in 20.4% on lower limbs. Melanoma from pigmented ne vus from childhood was confirmed on the trunk in 50.7%, but only in 5.6% on the face. We can observe the increasing occurrence of melanoma on a trunk according to the dura tion of the previous lesions -melanoma had arisen on the trunk from lesions in the duration of 0-4 years in 33.6%, in the duration of 5-9 years in 41.3%, in the duration over 9 years in 44.5%, and since childhood in 50.7% as mentioned above. Regarding the duration of lesions since childhood, we confirmed that 540 patients (19%, 2810 patients = 100%) suffered from nevus pigmentosus from childhood.
Some of our results are in contrast to other studies. There is a universal agreement that the incidence of mel  anoma diagnoses is increasing and a similar trend has been observed in Europe (21,22). 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 (23)(24)(25) More recent studies (1992)(1993)(1994)(1995)(1996)(1997)(1998)(1999)(2000)(2001)(2002)(2003)(2004)(2005)(2006) reported that melanoma incidence increased 3% to 4% per year across most demographic groups (1,26). How ever, a recent study of the Centers for Disease Control and Prevention database suggests that incidence in New Eng land states may be decreasing (27). Finally, it has been suggested that the observed in creased melanoma incidence may be an artifact of under reporting in earlier decades (28). Most of the studies cited above relied on SEER and National Program of Cancer Reg istries data to compare melanoma rates at different time points (29). Many previous epidemiologic studies were missing data on tumor thickness, and many registries did not capture in situ lesions (30,31). These factors could account for an underrepresentation of thicker melanomas and overestimation of mortality from thin melanomas.
According to some studies, males are approximately 1.5times more likely to develop a melanoma than females but the different prevalence in both sexes must be ana lyzed in relation to age: the incidence rate of melanoma is greater 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 than in women (32)(33)(34). Ac cording to other studies, higher melanoma rates have been mostly observed in elderly or male populations, whereas the female sex seems to represent an independent risk factor for early onset melanoma for women younger than 45 years (35)(36)(37). According to recent data, the rising mel anoma trends mostly affect the older age groups, where as the incidence seems to stabilize in the youngest age groups (24-44 years) (38). However, melanoma still affects mostly younger patients, with a median age diagnosis of 57-64 worldwide (38). This is in agreement with our study, the average age of new melanoma is 59-62 years according to our results.
Regarding the body site of melanoma, our study shows, that women suffer significantly more often from melano ma on lower limbs and on upper limbs, men suffer signif icantly more from melanoma on the trunk. According to some studies, the anatomical location of melanoma also varies according to gender. Males tend to have worse clin ical and histological characteristics at primary diagnosis; melanomas in men are more often located on the head, neck, and trunk, commonly ulcerated and have a higher Breslow thickness (39,40). Males are more likely to report greater exposure to the sun, mainly due to greater partic ipation in outdoor work and leisure activities, compared to females (41). Females are likely to be more knowledgea ble about skin cancer than males (42). However, the high er knowledge and use of sun protective measures among women conflicts with findings that women have a greater desire for a tan and their increased perception that a tan is healthy compared with men (31,43). Two pathways have been hypothesized for the development of cutaneous melanoma: one typically affects the head and neck, a site with chronic sun damage, and the other affects the trunk, which is less exposed to the sun. These results appear to support the hypothesis of divergent pathways to melano ma and that recreational sun exposure and indoor tanning are associated with melanoma on the lower limbs, the most common site of melanoma in women. These findings appear to have important preventive implications (44,45). This is in agreement with our results, that women suffer significantly more often from melanoma on lower limbs (31.8% of women versus 11.5% of men), men suffer signif icantly more often from melanoma on the trunk (58% of men versus 31.6% of women).
In our study we confirmed that melanoma had origi nated from nevus pigmentosus from childhood in 540 pa tients (19%) -on the trunk in 50.7% of patients, in 5.6% of patients on the face. According to the literature, approx imately 25-33% of cutaneous melanomas derive from a benign, melanocytic nevus, whereas this percentage may be as high as 50% in patients with numerous nevi (17,(46)(47)(48). Transformation of nevi to melanoma occurs most commonly in nonchronically sundamaged skin. Nevusprone patients with an increased number of mel anocytic nevi tend to develop melanomas at a younger age and on axial locations. On the other hand, nevus resistant patients with fewer nevi tend to develop de novo melano mas on habitually sunexposed skin or at older ages (49,50). There is a strong evidence that an intermittent pat tern of sun exposure increases the melanoma risk. Chron ic sun exposure shows no association or a weak inverse association with melanoma risk -it can explain the rare occurrence of melanoma from pigmented nevus from childhood on the face observed in our study. Episodic, in termittent, high-intensity exposure to sunlight has been linked to the development of melanoma in Australia (5,6). Total lifetime sun exposure is positively associated with melanoma risk, but the relationship is weaker than that for intermittent sun exposure (32,33,51,52). Sunburn is a marker of an intermittent pattern of sun exposure and there is a tendency for greater consistency of positive associations for sunburn than for intermittent exposure (32-35, 51, 52). Furthermore it may explain our results, as we suppose, that melanoma resulting from the nevus pigmentosus from childhood could be sunburned on the trunk, but there is chronic sun exposure on the face. Mel anoma risk differs not only by a pattern of sun exposure but also by body site, age, and phenotype of a patient (36,49). According to some studies, head and neck melano mas have been linked to chronic sun exposure with older age of diagnosis and melanoma on the trunk and limbs to younger ages and intermittent exposure. According to another study, sun exposure can cause melanoma on all body sites, but risks tend to be higher for usually sunex posed sites than occasionally exposed sites (37,53). For sunburn, strong positive associations have been found at all body sites (head/neck, trunk, arms, and legs) and with no significant sitespecific differences in a recent me taanalyses and pooled analyses (37,38,54). In our study, we confirmed a significant relation between the histology and body site of melanoma. Our study shows that lentigo maligna, melanoma in situ, melanoma nodulare, and mel anoma superficiale are found to be from 45.2% to 47.6% on the trunk, but lentigo maligna is found more often on a face (29.3%) and less often on lower limbs (9.6%), mela noma in situ only in 7.2% on a face, but in 20.4% on lower limbs. Melanoma nodulare was confirmed only in 12.7% of patients on the face, but in 19.5% and 21.6% of patients on upper and lower limbs respectively and in 46.2% of pa tients on the trunk. According to the literature, in con trast to cutaneous superficial spreading melanoma, the occurrence of nodular melanoma and mucosal melanoma seems to be independent of UV exposure. Specifically, in the case of nodular melanoma, the influence of UV is controversially discussed in the literature. Some studies reported a higher prevalence of nodular melanoma on sunexposed skin such as the lower limbs, head, and neck. However, nodular melanoma can also affect nonchron ically sunexposed body areas such as the trunk in fair but also darkskinned patients (48,(55)(56)(57).
Individuals with large or giant congenital melanocytic nevi (CMNs) at birth are at higher risk of melanoma de velopment which increases according to the size of CMN and is the highest in those nevi traditionally designated as garment nevi (58)(59)(60). Also, personal history of a pri or melanoma is a strong predictor for the development of a subsequent melanoma, with approximately tenfold increased risk (61). Additionally, melanoma seems to ap pear more commonly in immunosuppressed patients, in cluding patients with prior organ transplantation, hema tologic malignancies, or human immunodeficiency virus infection, as well as patients taking immunosuppressive medication (62).
The epidemiologic, genomic, and anatomic profiles of melanoma significantly differ across the world and mostly depend on a constellation of environmental and (epi) ge netic factors (11).The purpose of our study was to contrib ute to the evaluation of the incidence of melanoma in East Bohemia region in the Czech Republic in middle Europe and to evaluate the relation between the followed param eters.

CONCLUSION
No statistical difference in the occurrence of new melano mas during the period 2002-2017 was found, furthermore, no difference in the age of patients with melanoma; also there is no difference in the occurrence between men and women. The difference between men and women was not confirmed in histology, but the difference between men and women was confirmed in the body site of lesion and in the length of duration of lesion. Women suffer signifi cantly more often from melanoma on lower limbs and on upper limbs, men suffer significantly more from melano ma on the trunk. The length of the duration of lesion of 0-4 years to the diagnosis of melanoma was confirmed in 54.5% of women, but only in 46.5% of men. No relation be tween the length of duration of lesions from which mela noma had originated and its histology was confirmed. The relation was confirmed between histology and body site of melanoma. The increasing occurrence of melanoma on the trunk according to the duration of the previous lesions was confirmed.