The link between anthropometric indices, including height, and cancer risk and/or progression has attracted considerable interest in recent years. Adult height results from the complex interplay between genetic, hormonal, nutritional, and other environmental factors and has been found to contribute to the risk of several selected malignancies, although it has not been implicated as a real cause per se. A number of studies have investigated the height-melanoma relationship, showing controversial results so far. In this review, we summarize the epidemiological data regarding the association between height and melanoma risk and analyze the potential underlying mechanisms.
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In recent years there has been growing interest in investigating the link between anthropometric measures and cancer risk and progression. Height is included among these measures and has been suggested to contribute to the risk of several selected malignancies, although it has not been implicated as a real cause per se. Adult attained height might indeed be an indirect marker resulting from shared mechanisms within the complex interplay between genetic, hormonal, nutritional, and other environmental factors [ 1 ]. Epidemiological studies have also connected the risk of skin cancer to multiple anthropometric parameters, including height, but the results appear to be still controversial and the possible mechanisms underlying the positive association remain unclear.
Cutaneous melanoma is a potentially lethal malignancy derived from melanocytes, whose incidence has steadily increased worldwide over recent decades. The main risk factors include exposure to ultraviolet rays (UVR), number of common and atypical nevi, UVR sensitivity-related phenotypic characteristics, genetic susceptibility, and a family history of melanoma [ 2 ].
We conducted a narrative review to summarize the epidemiological data regarding the association between melanoma risk and height. Underlying mechanisms that might explain this association are also discussed.
Literature searches were performed in PubMed and Google Scholar databases up to September 30, 2018, using the terms “skin cancer,” “melanoma,” and “height.” Case-control and cohort studies that investigated the association between cutaneous melanoma risk and height were considered and selected after reading the title and abstract and, when appropriate, the full text. Only articles written in English were chosen. Additional studies were found among the references of the retrieved articles.
Results are described in separate sections depending on whether they were obtained from studies evaluating the risk of cancer at multiple sites, also including melanoma, or analyzing the risk of melanoma only.
Studies Assessing Cancer at Multiple Sites, Including Melanoma
Several studies have examined the cancer-height relationship and disclosed a significant positive association of adult height with both the overall cancer risk and the incidence of cancer at various anatomical sites, also highlighting a significant association between height and melanoma in both men and women [ 3 – 6 ].
Results from a prospective cohort study in subjects living in the area of Washington State indicated a hazard ratio for melanoma per 5 inches of height of 1.28 with a 95% confidence interval (CI) of 1.05–1.55, after adjustment for age, sex, and race [ 3 ]. In the Institutes of Health-AARP Diet and Health Study, the hazard ratio per 10-cm increase of height was 1.18 (95% CI 1.13–1.23) in males and 1.14 (95% CI 1.05–1.24) in females, after adjustment for covariates (age at entry, education, race, smoking status, and body mass index) [ 5 ].
The relation between height and cumulative relative risk of cancer appeared to be similar in different populations, with little difference across North America, Europe, Australasia, and Asia [ 7 ]. When height was handled as a time-dependent covariate, the results for all cancers combined and melanoma did not differ from those obtained using only baseline height [ 8 ].
Melanoma was among the highest ranking sites across the studies that included women and also among men, even after controlling for potential confounding variables, such as body mass index [ 4 , 7 , 9 ]. In a large prospective study involving 7 cohorts in Austria, Norway, and Sweden [ 4 ], increased height (per 5-cm increment) was associated with a higher global cancer risk and, among the different cancer types, melanoma had the highest hazard ratio in both women (1.17, 95% CI 1.11–1.24) and men (1.12, 95% CI 1.08–1.19).
Height was considered an important explanatory factor accounting for 33.8% of the excess risk of incident cancer for men vs women overall and for specific anatomical sites, and this was particularly evident also for melanoma, where the proportion mediated by height was 57.3% [ 3 ].
Influence on Mortality
Adult height appears to have opposite relationships with risk of death from various major causes of chronic diseases and cancer [ 11 ].
In the pooled cohort study carried out by Wirén et al [ 4 ], height was associated with a nonsignificant increase in the risk of death from cutaneous melanoma in both men and women (hazard ratio per 5-cm increment in height of 1.10 [95% CI 0.99–1.21] and 1.09 [95% CI 0.92–1.29], respectively).
An analysis of multiple prospective cohorts involving more than 1 million adults, mostly from Europe and North America, showed a hazard ratio per 6.5-cm greater height of 1.26 (95% CI 1.12–1.42) for risk of melanoma death, corresponding to the highest relative risk of cancer death in women and men combined [ 11 ].
In a prospective study, more than 18,000 London-based male government employees were followed up for mortality for a maximum of 35 years [ 12 ]. Following adjustment for covariates, taller men experienced elevated mortality rates from cancer of combined sites and from certain organ-specific malignancies. There was a significant association between height and mortality rate from skin cancer, defined as “malignant melanoma of skin” combined with “other malignant neoplasms of skin” (hazard ratio per 5-cm increase in height 1.35, 95% CI 1.06–1.70).
Studies Specifically Focusing on Melanoma
Various case-control and cohort studies analyzed the relation between anthropometric factors, including height, and melanoma risk selectively. Table 1 reports the general characteristics of the studies that focused on the risk of melanoma in association with adult height [ 13 – 25 ]. All these studies analyzed the risk of melanoma only, with the exception of one [ 24 ] that evaluated the risk of keratinocyte cancers and melanoma.
General Characteristics of the Studies Focusing Specifically on Melanoma Risk
Table 2 summarizes the results concerning the association between melanoma risk and height. Despite their methodological heterogeneity, many reports suggested an increased risk of melanoma with increasing height [ 13 – 15 , 18 , 21 – 23 , 25 ]. On the contrary, other studies failed to disclose a significant association [ 16 , 19 , 20 , 24 ]. Shors et al observed no association between melanoma and height in women but found an increased risk for men in the highest vs the lowest quartile (odds ratio 2.4, 95% CI 1.3–4.5), although these results were attenuated after adjustment for weight (odds ratio 1.9, 95% CI 0.9–3.8) [ 17 ]. It is interesting that prospective studies involving large cohorts linked to national cancer registries and followed up for many years consistently reported a significant trend in melanoma-height association [ 13 , 15 , 21 , 25 ].
Studies Focusing Specifically on Melanoma Risk: Summary of Results Regarding Association With Height
Stenehjem et al recently published the results of a prospective study aimed at assessing the risk of melanoma according to anthropometric factors, adjusted for exposure to UVR, in a large population-based cohort in Norway, linked to the national cancer registry, over an average follow-up period of 27 years [ 25 ]. They found significant positive associations for height, with greater than 50% increased melanoma risk for the highest quintile compared with the lowest quintile in both sexes. Height above the median was estimated to account for 10% of the male and 6% of the female melanoma cases, respectively. The authors also used restricted cubic splines for the assessment of melanoma risk. The shape of the risk curve appeared to support an exponential increase. The risk according to height increased with statistical significance until 195 cm in men and from approximately 170 to 180 cm in women, and then declined.
Results from a cohort of French women indicated that melanoma risk was positively associated with height in age-adjusted models only, as well as with sitting-to-standing height ratio in multivariable models, while no significant association with sitting height or leg length was observed [ 23 ].
In the pooled analysis of melanoma in women performed by Olsen et al [ 22 ], there was an increased risk of melanoma in the highest quartile of height compared with the lowest quartile for women overall (pooled odds ratio 1.3, 95% CI 1.1–1.6). After stratification by age, the association was limited to women <50 years of age (pooled odds ratio 1.4, 95% CI 1.1–1.9). Elevated odds ratios in the highest quartile of height were found for superficial spreading melanoma (pooled odds ratio 1.3, 95% CI 1.0–1.7), and to a lesser extent for nodular melanoma (pooled odds ratio 1.2, 95% CI 0.7–2.1), whereas no association with lentigo maligna melanoma was observed. Furthermore, increased risks associated with the highest quartile of height were noticed for melanomas of the head/neck, lower limbs, and upper limbs [ 22 ].
According to Thune et al [ 15 ], there was a positive association with height for melanomas localized on the face and trunk in both sexes, and for those of the lower limbs only in females. Stenehjem et al described significant positive trends for trunk, head, and neck melanomas in men, and for melanomas of the upper and lower limbs in women, and, as concerns the relation between height and histological subtype, they observed significant dose-related risks for superficial spreading melanoma and nodular melanoma in both sexes [ 25 ].
With regard to the studies shown in Table 1 , a great heterogeneity is recognizable among them, in terms of design, sample size and characteristics, as well as adjusted confounding factors. Limitations of most studies were the lack of complete information on several variables known to be risk factors for cutaneous melanoma and consequently the inability to adjust for the potential confounding effect of such variables. For instance, only some studies included adjustment for sunlight exposure, sun sensitivity (eg, sunburn) and/or UVR indicators, hair color and/or other pigmentary traits, and number of nevi ( Table 1 ). Nevertheless, such information was categorized using nonstandardized and heterogeneous definitions, especially in the case of nevi count and sunlight exposure. Lahmann et al took into account in their model clinical elastosis of the neck as an indicator of sun sensitivity and cumulative sun exposure [ 24 ]. In very few studies, data on family history of melanoma, other skin cancers or malignancies, or personal history of nonmelanoma skin cancer were available and taken into consideration ( Table 1 ).
In the analysis performed by Kvaskoff et al [ 23 ], the positive association between height and melanoma, detected in age-adjusted models only, was weakened and lost any statistical significance after full adjustment for age and also for other known risk factors for melanoma. In particular, the factors that decreased the strength of this association were number of nevi and hair color. The associations revealed by Olsen et al were instead unaffected by adjustment for other known melanoma risk factors, such as sun exposure-related features [ 22 ].
Many other factors may act as confounders, including ethnicity, socioeconomic status, education, outdoor activity, smoking, tanning habit, use of sunbeds, and other lifestyle factors, and these were taken into consideration occasionally ( Table 1 ).
Moreover, the majority of studies have relied on self-reported height, thus impairing the accurateness and precision of data entry [ 1 ]. In fact, only a limited number of reports clearly indicated that measurement of height was obtained by trained staff [ 15 , 21 , 24 , 25 ]. Inaccuracy of estimates might also be related to recall bias, when the self-reporting of height was done in different periods of time, or to the assessment of height after the occurrence of cancer in case-control studies [ 22 , 25 ].
It is relevant to underline that a recent systematic review and meta-analysis gave evidence for the relationship between height and melanoma risk [ 26 ]. The authors included 12 prospective studies, most of which enrolled Caucasian populations with a total of 4,723,739 participants and 20,049 cases of melanoma. Different potential confounding factors were taken into account for multivariate regression analyses in the included studies. In brief, the cumulative findings of this meta-analysis indicated that subjects in the top category of height had increased risk of melanoma (random-effects relative risk 1.46, 95% CI 1.24–1.73; P < 0.001) compared with the lowest category. Per 10-cm increment in height was positively correlated with increased melanoma risk (random-effects relative risk 1.27, 95% CI 1.19–1.35; P < 0.001), with significant results seen in both women and men using a subgroup analysis by gender.
Meyle et al examined anthropometric parameters in childhood (measured at ages 7–13 years) in relation to future risk of melanoma. For this purpose, they analyzed the data of 372,636 Danish children from the Copenhagen School Health Records Register, during approximately 11 million person-years of follow-up [ 27 ]. Relevant strengths of this study were the large sample size, the minimal loss to follow-up, the absence of selection bias, the inclusion of carefully recorded height measurements, and the identification of melanoma cases via linkage to the national cancer registry. Greater childhood height at the ages of 7 and 13 years was shown to be significantly associated with an increased risk of melanoma in adulthood. Melanoma risk was also associated with birth weight. Therefore, the authors concluded that associations between body size and melanoma may initiate early in life and can be related to height and birth weight, without any apparent influence of body mass index or body surface area [ 27 ].
A further analysis of the same cohort revealed the positive and significant association of childhood height with the majority of melanoma variants in adulthood (superficial spreading melanoma, nodular melanoma, melanoma not otherwise specified), but not with lentigo maligna melanoma [ 28 ].
Putative Mechanisms Underlying Height-Melanoma Relationship
In various analyses, positive height–cancer gradients were disclosed for many cancer types, including melanoma [ 3 – 10 ], suggesting that factors related to height might contribute to cancer development in adulthood. The observations that height can be associated with selected cancers but not others seem to imply the existence of biological and behavioral mechanisms that vary depending on the anatomical site but may be shared by different cancer sites and/or types [ 3 , 8 ].
A number of hypotheses have been proposed to explain the association between height and melanoma.
Human growth is a complex phenomenon influenced by genetic, hormonal, nutritional, and other environmental factors from fetal life to puberty. The growth hormone (GH)–insulin-like growth factor (IGF)-1 axis plays a central role in growth. Nevertheless, numerous genes are involved in the control of stature, the large part of which are outside the GH–IGF-1 system, and many other molecules, as well as multiple intracellular molecular pathways, are involved in growth processes [ 29 ]. For instance, a meta-analysis of genome-wide association studies identified nearly 700 variants, reflecting 423 loci, that contribute to normal adult stature variation in individuals of European ancestry and can explain nearly 20% of the heritability for adult height [ 30 ].
Adult attained height is thought to be the consequence of the interplay of genetic factors and many early-life experiences and exposures that may have an impact on cancer or other pathological events occurring much later in life. Stature may be an indirect indicator of nutritional status or caloric intake during childhood or adolescence [ 31 ]. A few data have suggested that caloric restriction during development can have lasting beneficial effect on the future risk of malignancy [ 32 ].
It has been postulated that cancer risk is proportional to organ cellularity and the number of proliferating cells within tissues [ 3 , 31 ]. Height is directly correlated with the number of cells that can be susceptible to convert into neoplastic cells, and, for melanoma, the number of melanocytes is relevant, as well as the total body area. Some authors detected a positive association between melanoma risk and high body surface area [ 15 , 25 ], while others noted no relation with body surface area [ 22 , 23 ]. As concerns nevus number, Ribero et al highlighted the importance of growth in melanoma susceptibility based on the results of a study in the TwinsUK cohort that disclosed the positive association between nevus count, an important risk factor for melanoma, and height [ 33 ]. Moreover, their study also revealed that nevus count was unrelated to weight and positively associated with bone mineral density. Adjustment for leukocyte telomere length, known to be linked to both bone mineral density and nevus count, did not modify the significance of the association between height and nevus count, thereby ruling out a direct influence of leukocyte telomere length on the results [ 33 ].
Height is correlated with hormones and growth factors that may also be involved in carcinogenesis. The IGF system plays an important role during the peripubertal growth spurt, and the peak in height velocity at adolescence is driven by a cascade of hormones, primarily initiated by a rise in sex steroids and followed by increases in GH and the related IGF-1 [ 34 ]. IGF-1 level in children was found to be positively associated with growth in height [ 35 ]. Moreover, the GH–IGF-1 axis can be influenced by nutritional status [ 36 ]. IGF and GH have been implicated not only in tissue growth and development, but also in carcinogenesis [ 37 ]. Results from prospective studies of individuals with acromegaly have reported increased risks of melanoma [ 38 ]. GH exerts multiple biological effects directly or through IGF-1 action and can interfere with many intracellular signaling pathways known to be implicated in oncogenesis [ 37 ]. Of interest, human melanoma cells have been found to express GH receptors and also human metastatic melanoma cells were shown to possess active GH receptors that can modulate multiple signaling pathways capable of promoting tumor progression [ 39 – 41 ]. In addition, experimental data have supported the regulatory role of IGF axis in human melanoma, particularly in the proliferation of early-stage melanoma cells [ 41 – 43 ].
Previous case-control studies have examined the association between circulating IGF-1 concentrations and the risk of melanoma with inconsistent results [ 44 , 45 ], while a nested case-control study in a prospective cohort from 10 European countries did not find any significant association between circulating IGF-1 concentration measured in adulthood and melanoma risk [ 46 ]. However, these findings do not necessarily rule out the influence of IGF-1, especially during childhood, on the future risk of melanoma. As previously mentioned, the achieved height can be correlated with the level of serum IGF-1 in puberty, but later any correlation may be lost. Growth-influencing exposures during childhood, which operate also through effects on IGF-1 levels, may have long-term influences on disease risk, without, however, conditioning IGF-1 levels throughout life [ 47 ]. In this context, prepubertal age is likely to be a crucial period in determining the risk of melanoma in adulthood, as suggested by the effects of sunburn and UVR exposure at these ages on nevogenesis and melanomagenesis [ 48 ].
A recent hypothesis has taken into consideration body-resonant radiation that may affect both cancer incidence and body height. Radio-waves might influence body height through hormonal disturbances. It has been speculated that individuals who sleep in a bed that acts as a radio-wave antenna can be particularly prone to the harmful effects of radiation. Therefore, a correlation between melanoma incidence, mean body height, the number of FM broadcasting transmitters, as well as the use of metal spring mattresses has been hypothesized [ 49 ].
Accumulating evidence suggests the relation between anthropometry and cancer. A positive association between height and melanoma risk has been suggested, although results appear to be still controversial. However, the existence of a significant association has been highlighted in a recent systematic review and meta-analysis [ 26 ].
Further research is, however, required to confirm a height-melanoma relationship and better understand the underlying mechanisms. An intriguing aspect is the identification of the possible shared genetic factors and pathomechanisms, as well as exposures occurring early in life that are capable of influencing both growth process and future cancer risk.
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