Etiology and Pathogenesis 361 etiology

As in younger patients, little is known about the causes of cancer in adolescents and young adults. It is likely that environmental agents contribute to the great majority of cancers in older age groups following chronic exposures over many years [41], but in the young there is no opportunity for such long-term exposures. The mechanisms operating between exposure to a risk factor and clinical onset of a cancer in the young may, therefore, be fundamentally different compared with late-onset cancers. In addition, the contributions of the various factors may be proportionally very different and it is likely that genetic susceptibility plays a greater role.

Whereas cancers in infants and young children are likely to be influenced strongly by congenital and prenatal factors, and cancers in the elderly are most strongly linked with environmental causes, the cancers in adolescent and young adult patients may be an interesting combination of both. It has been possible to attribute only very few cancers in this age group directly to single environmental or inherited factors. An exception is clear-cell adenocarcinoma of the vagina or cervix in adolescent females, with most cases caused by diethylstilbestrol taken prenatally by their mothers in an attempt to prevent spontaneous abortion [42]. Radiation-induced cancer may occur in adolescents and young adults after exposure during early childhood; rates of thyroid cancer in children and adolescents have increased in Eastern European and Slavic countries since the Chernobyl accident in 1986 [43]. In fact, many of the adolescent and young adult cancers that have been linked to etiologic factors are second malignant neoplasms in patients who were treated with chemotherapy and/or radiotherapy for a prior cancer.

Given that the duration of exposure to potential environmental carcinogens is proportional to age, it is not surprising that tobacco-, sunlight-, or diet-related cancers are more likely to occur in older adolescents and young adults than in younger persons. Nonetheless, these environmental agents known to be carcinogens in older adults have not been demonstrated to cause cancer with any significant frequency in adolescents. It appears to take considerably longer than one or two decades in most persons for these environmentally related cancers to become manifest. The logical hypothesis is that adolescents who develop cancer after a carcinogenic exposure have a predisposing genotype. For example, melanoma is more common among Australian adolescents than elsewhere in the world, as described above. This suggests that solar exposure may be able to induce skin cancer before the end of the second decade of life, at least in that part of the world. That melanomas during adolescence usually occur in nonexposed areas of the body mitigates against this explanation, and may suggest that the epidemiology of melanoma in Australia is determined more by genetic factors than environmental exposures (cf. Chapter 17).

Besides intense sun exposure, exposure to other environmental carcinogens begins or intensifies during this age period: tobacco use, recreational drug use, alcohol use, and sexually transmitted disease. It is unlikely, however, that cancers resulting from these exposures occur during young adulthood. They are much more likely to occur later in life.

There is accumulating epidemiological evidence that childhood precursor B-cell ALL, which demonstrates a characteristic peak in incidence between the ages of 2 and 6 years, is etiologically linked to delayed exposure to infections in early childhood, resulting in delayed immune stimulation. There is also strong evidence that an initial mutational event occurs in utero and predisposes the child to subsequent development of leukemia in early life [44-48]. Spacetime clustering patterns in childhood leukemia also support a role for infections [49]. The decrease in incidence rates in ALL with increasing age following the childhood peak to young adulthood suggests that etiological factors and/or mechanisms may also change with age. Nevertheless, infections may play an important role in the etiology of leukemia in adolescents and young adults, but whereas in young children mainly indirect mechanisms have been proposed, in these older age groups a directly transforming virus may be more likely [50].

With respect to AML, the increased risk following exposure to certain therapeutic agents used to treat an initial malignancy [51] (i.e., chemical induction of AML) suggests the possibility of a role for environmental chemical exposures in a proportion of cases in young people in general. Higher rates for AML were seen with increasing age among adolescents and young adults, and there was some evidence of an increase in incidence rates over time. The possibility that these patterns of incidence might be due at least in part to postnatal exposures to environmental chemical agents should be given some consideration.

Viruses may also be involved in the etiology of both NHL and Hodgkin lymphoma. An increased risk of NHL has been observed in association with HIV1, HTLV1 and Epstein-Barr virus (EBV). Helicobacter pylori infection of the stomach is associated with gastric lymphoma. While these are all relatively rare occurrences and probably account for only a small proportion of total NHL, a role for other viruses and indirect mechanisms involving common infections remain a possibility [52]. EBV infection is linked etio-logically to a proportion of Hodgkin lymphoma, particularly the mixed-cellularity subtype. Epidemiologi-cal studies have demonstrated that the magnitude of the risk and proportion of cases attributable to EBV infections varies with age, sex, ethnicity, and level of material deprivation. EBV infection is extremely common and other unknown modifying factors are likely to be of importance in the etiology of Hodgkin lymphoma in adolescents and young adults [53, 54].

The decline in the incidence of PNETs, the increase in high-grade astrocytomas, and decrease in low-grade astrocytomas with increasing age may reflect a change in etiological mechanisms in these tumors. A possible role of polyoma viruses, including simian virus 40 (SV40), JC, and BK viruses in CNS tumors has been the subject of much speculation. Viral DNA sequences have been detected in human brain tumors, including PNETs, ependymomas, high- and low-grade astrocytomas, and meningiomas [55-57]. In addition, spacetime clustering has been detected in astrocytomas and ependymomas in older children [58]. Presence of space-time clustering is consistent with an infectious etiology. Furthermore, there are similar temporal trends in the incidence of brain tumors in children, adolescents, and young adults [4, 59]. It follows that there may be shared etiological factors for certain brain tumors across these age groups. Hypotheses relating to viral exposures should be investigated.

The increasing ratio of male to female cases across the three age groups 13 to 14 years, 15 to 19 years, and 20 to 24 years suggests that the onset of osteosarcoma and Ewing tumor may be associated with the adolescent growth spurt, which occurs earlier in females than in males. Dietary and hormonal factors may be relevant. The possibility of a viral etiology for osteosarcoma has also been considered, and SV40-like sequences have been detected in osteosarcoma tissue in several studies [60-63]. In the most recent of these studies, the frequency of SV40-like sequences in peripheral blood cells from osteosarcoma patients was compared with that in normal, healthy controls and was found to be substantially increased in the osteo-sarcoma patients [63]. Space-time clustering has been reported in childhood STS [64]. It would be of considerable interest to determine whether STS in adolescents and young adults exhibit space-time clustering.

The very marked temporal increase in incidence of testicular germ cell tumors in young men has been reported previously. The etiology of testicular germ cell tumors is uncertain, but genetic and hormonal factors, including in utero exposure to estrogen, appear to be implicated [65]. A recent cohort study of young men in Sweden found a positive association between height at 18 years and the incidence of testicular cancer that was not accounted for by gestational age and birthweight. The authors concluded that factors influencing postnatal growth such as diet or growth-related genes might underlie the association [66]. The incidence trends for melanoma of the skin have also been discussed previously. Melanoma of the skin shows associations with socioeconomic factors, skin and hair coloring, certain heritable syndromes, and in particular, patterns of sun exposure [65].

The pattern of carcinomas in adolescents and young adults differs greatly from that seen at older ages. Carcinomas of the head and neck, including thyroid and nasopharynx, make up nearly 30% of carcinomas in the 13- to 24-year age range. The temporal increase in carcinoma of the thyroid in young people has been discussed elsewhere [4]. The highest incidence rates for NPC are found in parts of the Far East where it occurs in association with EBV infection. The rare cases of NPC in young people in Western developed countries may also be associated with EBV, and this should be explored, but it is likely that other cofactors are involved [67]. Carcinoma of the cervix and uterus, although typical of older age groups, is relatively frequent in young adult females and appears to be closely linked with sexually transmitted infections including herpes simplex virus type 2 and human papilloma virus [65]. Other carcinomas seen in adolescents and young adults that occur typically in later life may be strongly associated with genetic predisposition at young ages, as will be discussed below.

How To Prevent Skin Cancer

How To Prevent Skin Cancer

Complete Guide to Preventing Skin Cancer. We all know enough to fear the name, just as we do the words tumor and malignant. But apart from that, most of us know very little at all about cancer, especially skin cancer in itself. If I were to ask you to tell me about skin cancer right now, what would you say? Apart from the fact that its a cancer on the skin, that is.

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