Abstract
Sinonasal cancer, the cancer of the nose and paranasal cavities is a rare type of cancer. Its incidence varies between men (0.5–1.5 new cases annually per 100,000) and women (0.1–0.6/100,000) and also from country to country. These variations in incidence are mostly explained by differences in occupational exposure, in particular exposure to wood dust, which is by far the major risk factor. This chapter gives an overview of studies on sinonasal cancer dealing with epidemiological findings and various occupational risk factors, exposure levels and other exposure characteristics, tumor pathology, the molecular cancer mechanisms likely to be involved in the development of the disease, and, finally, molecular alterations observed in tumors and available as potential molecular markers. The main studies and their findings as well as the principal pathological features of sinonasal tumors are summarized in tables and exemplified in illustrations.
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Keywords
- Sinonasal cancer
- Epidemiology
- Pathology
- Occupational factors
- Wood dust exposure
- Genotoxicity
- Molecular markers
- Mechanisms of carcinogenesis
Introduction
Sinonasal cancer, the cancer of the nose and paranasal cavities (ICD 10 codes C30.0 and C31.0 to C31.9), is a rare form of cancer. Its incidence varies between men (0.5–1.5 new cases annually per 100,000) and women (0.1–0.6/100,000) and also from country to country. For example, age-standardized incidence rates among men during 1998–2002 in some European countries were 0.8–1.6 in France, 0.4–1.4 in Italy, 0.9 in Denmark, 0.8 in the Netherlands, 0.8 in Norway, 0.3–0.7 in the UK, 0.5–0.6 in Germany, 0.5 in Finland, and 0.4 in Sweden; in the USA the incidence rate was 0.7 (in Blacks) and 0.6 (in Whites). The corresponding rates in each country were lower for women [1]. There has also been some variation in the incidence rates over time [2–4]. It is currently seen that by far the most important factor explaining such variation in incidence is exposure, in particular occupational exposure, whereas individual factors, such as genetic susceptibility, play only a very minor role [2, 4].
Anatomically, the sinonasal region is located in the midportion of the face and is composed of the centrally located paired nasal cavities surrounded by paired paranasal sinuses (maxillary, frontal, ethmoidal, and sphenoidal) (Fig. 7.1) [5]. The airspace within the sinuses is connected to that of the nasal cavities via narrow passages.
Nasal cavities and paranasal sinuses shown in (a) coronal and (b) transverse sections. The orientation of the sections is illustrated in the middle where the frontal sinus is also shown. The ethmoidal labyrinth is a frequent target of sinonasal adenocarcinoma (Adapted from Gnepp [5])
In the most anterior part of the nasal cavity, the superior and lateral walls are composed of the soft tissues of the nasal wings; this area is called the nasal vestibule. The lining of the vestibule consists of an extension of the skin with keratinizing stratified epithelium and secondary appendages. This lining extends 1–2 cm from the external rim of the nose into the nostrils. The mucocutaneous junction is the location where the respiratory mucosa (referred to as the Schneiderian membrane) begins. The nasal cavity with the turbinates and the paranasal sinuses are lined with this epithelium. The superior, middle, and inferior turbinates (conchae) hang into the nasal lumen along the lateral wall of the nasal cavity. Posteriorly, the turbinates end approximately one cm anterior to the choanal orifice where the nasal cavity leads into the anterior opening of the nasopharynx.
The ethmoid labyrinth in the adult is a completely pneumonized complex of 3–18 cells per side. The roof of the labyrinth is adjacent to the anterior cranial fossa. The maxillary sinus is the largest of the sinuses, and it encompasses the majority of the body of the maxilla. The frontal and sphenoidal sinuses (Fig. 7.1) are of less importance for the topic of this chapter; these are described in more detail elsewhere [6].
This chapter will give an overview and discuss studies on sinonasal cancer dealing with epidemiological findings and various occupational risk factors, exposure levels and other exposure characteristics, tumor pathology, the molecular cancer mechanisms likely to be involved in the development of the disease, and, finally, molecular alterations observed in tumors and available as potential molecular markers. The main studies and their findings as well as the principal pathological features of sinonasal tumors are summarized in tables and exemplified in illustrations.
Epidemiology and Occupational Risk Factors
Sinonasal cancer is a rare type of cancer with 0.5–1.5 new cases per year per 100,000 in men and 0.1–0.6/100,000 in women. The incidence has been relatively stable in the last decades but varies markedly between the countries and even within the same country, from one region to another [7, 8] (see Introduction for some detail). Two main histological types of sinonasal cancer (squamous cell carcinomas and adenocarcinoma; see also Section on Pathology) exist with somewhat different etiologies and epidemiology. The 5-year relative survival of sinonasal cancer is about 50–60 % in Europe and the USA [8–12].
Occupational Risk Factors
Several occupational exposures are known to increase the risk of sinonasal cancer. According to the recent review of human carcinogens compiled by the International Agency for Research on Cancer [4, 13–15], wood dust, leather dust, nickel compounds, radium-226, and work in isopropanol production cause sinonasal cancer. Positive associations have also been observed between sinonasal cancer and exposure to chromium VI compounds, to formaldehyde, and work in the textile industry, although the evidence remains limited in humans [16]. The following Section on Exposure Characteristics characterizes the exposures involved, giving more detail in estimated numbers of those exposed at work, exposure levels, exposure-response relationships, as well as industries and occupations relevant.
Since sinonasal cancer is a rare disease, cohort studies may often lack the statistical power to detect even moderate excess risks. In addition, as many occupational cohort studies are based on mortality data, no reliable information on histology is available. Therefore, most information on risk factors for sinonasal cancer has emerged from case-control studies. For such a rare disease, however, even case-control studies tend to involve a relatively small number of cases (generally less than 100), precluding detection of associations with specific jobs or exposure to specific substances.
This section will thus focus on the results of a pooled reanalysis of 12 case-control studies on sinonasal cancer conducted in seven countries [17–19]. These studies were selected on the basis of the availability of information on histological type, age, sex, smoking, and occupational histories. The pooled dataset consisted of 930 patients with sinonasal cancer (680 men and 250 women) and 3,136 controls (2,349 men and 787 women). The cases included 195 adenocarcinomas (169 men, 26 women) and 432 squamous cell carcinomas (330 men, 102 women). The proportion of adenocarcinomas was distinctly higher in the studies carried out in France (49 %), Italy (between 22 and 69 %), and the Netherlands (25 %) compared to those performed in the USA (between 3 and 14 %). The occupational histories were coded and exposures were assessed through a job-exposure matrix. The main advantage of the pooled analysis is that it provides sufficient statistical power to realistically examine the risks according to histological type, sex, work, exposure category, and exposure duration.
The analyses from the pooled dataset focused on the associations with wood dust [17], formaldehyde, silica, textile dust, coal dust, flour dust, asbestos, man-made vitreous fibers [19], and various occupations and industries [18]. An analysis was also conducted restricted to the 8 European studies included in the pooled dataset, dealing with exposure to wood dust, leather dust, and formaldehyde [20]. The main characteristics of the 12 studies are summarized in Table 7.1. Specific results from the original studies as well as results from case-control studies not included in the pooled dataset (Table 7.2) or from cohort studies will be also presented and discussed when they add relevant information.
Wood Dust
The causal role of exposure to wood dust in the genesis of sinonasal cancer has long been unambiguously established by numerous epidemiological studies, carried out in populations in different geographical origin, who were exposed for different periods and in several fields of activity [2, 4, 14].
Demers and coworkers [17] analyzed the pooled data from 12 case-control investigations presented above and summarized in Table 7.1. Seven categories of woodworkers were investigated. The levels of exposure to wood dust were classified into 4 categories (none, low, medium, and high), corresponding approximately to the following estimated concentrations: equal to zero, less than 1 mg/m3, between 1 and 5 mg/m3 and above 5 mg/m3. The distribution of histological types varied markedly between studies.
Adenocarcinoma
The results from the pooled analysis [17] revealed that there was a sizeable risk of adenocarcinoma (Fig. 7.2). The study showed a high risk in men working with a wood-related job (OR 13.5; 95 % confidence interval [CI] 9.0–20.0). This risk was particularly high in the case of cabinetmakers and men employed in furniture factories (OR 41.1; 95 % CI 24.5–68.7). No increase in the risk of adenocarcinoma was shown for lumberjacks, foresters, or employees in paper pulp plants. The risk for saw mill employees was intermediate (OR 19.7; 95 % CI 11.1–35.1) and slightly lower after eliminating those who had worked in furniture factories (OR 14.9; 95 % CI 8.0–28.7).
Exposure to wood dust. Estimated relative risks from case-control (CC) studies (Forest plot) for sinonasal cancer associated with occupational exposure, by main histological types. Diamonds represent the estimated ORs, horizontal lines represent the 95 % CIs, and the size of the gray squares indicates the relative size of the study population in each stratum. OR, odds ratio; 95 % CI, 95 % confidence interval
For men, the risk of adenocarcinoma increased with the intensity of exposure (OR 0.6, 95 % CI 0.1–4.7 for low exposures; OR 3.1, 95 % CI 1.6–6.1 for moderate exposures; and OR 45.5, 95 % CI 28.3–72.9 for high exposures), and with exposure duration (OR 1.08, 95 % CI 1.07–1.09 per year; OR 5.3, 95 % CI 2.5–11.1 for duration shorter than 5 years; OR 10.7, 95 % CI 5.2–11.8 for duration of 10–19 years; and OR 36.7, 95 % CI 22.0–61.3 for duration of 30 years or more). The data provided evidence for a latency period, in the order of at least 20 years.
The results for women were less conclusive: the increase in the risk of adenocarcinoma for women with wood-related jobs (OR 2.78; 95 % CI 0.75–10.3) was smaller than that seen in men. As with men, the risk was greatest for women employed in furniture factories (OR 4.6; 95 % CI 1.16–18.3). No increase in risk was observed with an increase in the intensity of exposure in women, regardless of the histological type. However, the small number of cases precluded any detailed analysis.
Squamous Cell Carcinoma
The findings from the pooled analysis [17] were more ambiguous for squamous cell cancers than for adenocarcinomas (Fig. 7.2). The risk for women only was approximately doubled, particularly for women who had worked in moderately or highly exposed jobs; an exposure-effect relationship was evident with respect to the exposure duration. It has to be noted that the results for women were based on small numbers. For men, the risk of squamous cell carcinoma was not related to being exposed at the job nor to the intensity or the duration of exposure. Overall, the results showed the risk estimates for squamous cell carcinomas to be distinctly lower than those for adenocarcinomas.
Case-control studies not included in the pooled analysis confirmed the role of wood dust exposure in sinonasal cancer risk, the association with exposure to wood dust being much stronger for adenocarcinomas than for squamous cell carcinomas (Fig. 7.2).
Cohort Studies
An elevated risk of sinonasal cancer was also found in cohorts of woodworkers, but there was no information available on histological type. Demers and coworkers [56] performed also a pooled analysis of five cohorts of workers exposed to wood dust. A significant excess in the number of deaths from sinonasal cancer (11 cases; standard mortality ratio [SMR] 3.1; 95 % CI 1.6–5.6) was found, with a clear increase of the SMR with the exposure probability. The excess risk was limited to workers in the furniture industry and no sinonasal cancer deaths were observed in the plywood industry cohorts. The excess risk was limited to those workers who had begun their employment before 1940 and to those whose exposure had begun more than 20 years earlier. In this pooled analysis, the results were strongly influenced by the number of deaths from sinonasal cancer in the group of furniture industry workers from England (ten out of the 11 deaths from sinonasal cancer).
Summary of Studies on Wood Dust
There are epidemiological data indicating that exposure to wood dust is related to extremely high relative risks for sinonasal cancer. Adenocarcinoma represents a variable proportion of sinonasal cancers (between 10 and 50 %, depending on the country). The link between the onset of this histological form and exposure to wood dust is very clear and the association is stronger for adenocarcinomas than for squamous cell carcinomas. Thus, the excess risks reported for all the histological types together could be explained largely by the results relating to adenocarcinoma.
Even though the results for adenocarcinoma were on the whole consistent across the studies, the relative risk was much higher in Europe (especially France and Italy) than in North America and Asia. This difference could be related to the levels of exposure or to the types of wood in use, although no data on the type of wood used were available in the pooled analysis to confirm this hypothesis. However, hardwoods are more widely used in Europe, especially in southern countries, where the proportions of adenocarcinomas among sinonasal cancer cases are higher than in the north.
A large part of the adenocarcinoma cases included in the published studies were related to exposure to hardwood dusts, and the case-control investigations in which the type of wood used was evaluated confirm the suspicion of a stronger association with hardwood dust than with softwood dust [4, 22, 48]. However, it is virtually impossible to distinguish the respective role of each type of wood in the genesis of sinonasal cancer. On the one hand, very few studies have recorded the necessary information, and, on the other, rather often both types of wood are used in furniture factories and also in carpentry and cabinetmaking workshops, the fields of activity in which the risks are highest.
The results of some studies with workers exposed solely or mostly to softwood dusts showed a consistent excess risk, but the magnitude of the excess was small in comparison to hardwood, and the association was primarily with squamous cell carcinoma [4, 57].
Leather Dust
An excess of sinonasal cancers in leather workers, especially in boot and shoe manufacture and repair, has been reported in numerous case-control studies (Fig. 7.3), as well as in cohort or record linkage studies in the United Kingdom [58, 59], the Nordic countries [47, 60], and Italy [61]. The role of leather dust was suggested by the observation of higher risks in jobs exposed to dust and in workers most extensively exposed to leather dust. Leather dust is now considered as a human carcinogen (Group 1) by the IARC [4, 14] with sufficient evidence in humans for the nasal cavity and paranasal sinuses (see also Section on Exposure Characteristics). The association is stronger for adenocarcinomas, but some results suggest that other histological types could also be involved. Merler and coworkers [30] showed a very clear relationship between the level of exposure to leather dust and the risk of adenocarcinoma, with an OR of 20.4 (95 % CI 2.7–152.0) for moderate exposures and 88.0 [95 % CI 12.1–642.0] for high exposures. For the other histological types, the OR associated with exposure to leather dust was 6.9 (95 % CI 1.4–34.4).
Exposure to leather dust. Estimated relative risks from case-control (CC) studies (Forest plot) for sinonasal cancer associated with occupational exposure, by main histological types. Diamonds represent the estimated ORs, horizontal lines represent the 95 % CIs, and the size of the gray squares indicates the relative size of the study population in each stratum. OR, odds ratio; 95 % CI, 95 % confidence interval
Nickel and Chromium Compounds
The association between the occurrence of sinonasal cancers and exposure to nickel compounds encountered in nickel refining is well recognized. Excesses of sinonasal cancers have also been observed in cohorts of workers exposed to hexavalent chromium [4, 14, 62].
In case-control studies, exposures to nickel and chromium (often simultaneously) have emerged mainly from welding stainless steel, or spray painting, and the levels of exposure were low, which may explain the mainly null results (Figs. 7.4 and 7.5). However, Hernberg and coworkers [42] studying these exposures in these kinds of activities for sinonasal cancer observed an OR of 2.7 (95 % CI 1.1–6.6) for exposure to chromium and of 2.4 (95 % CI 0.9–6.6) for exposure to nickel. Other studies have not confirmed these results. Brinton and coworkers [34] observed a nonsignificantly increased risk of sinonasal cancer in those subjects exposed to chromates (OR 1.49; 95 % CI 0.40–5.60) through the use of these products in construction and painting. Only one male case was exposed to nickel in this study (OR 1.78; 95 % CI 0.10–27.6]. Two studies have examined the histological types separately [24, 38], and no significant association with exposure to chromium and nickel was observed, regardless of histological type. The results with regard to exposure to welding fumes were conflicting [24].
Exposure to nickel compounds. Estimated relative risks from case-control (CC) studies (Forest plot) for sinonasal cancer associated with occupational exposure, by main histological types. Diamonds represent the estimated ORs, horizontal lines represent the 95 % CIs, and the size of the gray squares indicates the relative size of the study population in each stratum. OR, odds ratio; 95 % CI, 95 % confidence interval
Exposure to chromium compounds. Estimated relative risks from case-control (CC) studies (Forest plot) for sinonasal cancer associated with occupational exposure, by main histological types. Diamonds represent the estimated ORs, horizontal lines represent the 95 % CIs, and the size of the gray squares indicates the relative size of the study population in each stratum. OR, odds ratio; 95 % CI, 95 % confidence interval
Formaldehyde
Formaldehyde is a probable cause of sinonasal cancer based on sufficient evidence from excess of squamous cell carcinomas in rodents and limited evidence in humans (with an overall evaluation of carcinogenic to humans, Group 1) [13, 63].
Following the reporting of nasal squamous cell carcinogenicity in rats exposed to high doses of formaldehyde in the early 1980s [64], several epidemiological studies have been published [2, 63]. Five cohort studies and one study of proportionate morbidity based on industrial formaldehyde exposure [65–73], and five studies based on exposures among pathologists and embalmers [74–78] have examined the association between formaldehyde and sinonasal cancer. The histological subtypes have not been specified in any of the cohorts. Due to the rarity of the disease, the observed and expected numbers in each study have been very small, and the interpretation of risk is therefore uncertain. A study of proportionate morbidity from Denmark, however, included 13 male and 4 female cases on nasal cavity cancer with corresponding estimated relative risks of 2.3 (95 % CI 1.3–1.4) and 2.4 (95 % CI 0.6–6.0) [69, 70].
The pooled data of 12 case-control studies were analyzed with respect to formaldehyde exposure [19] (Fig. 7.6). Significantly elevated relative risks for adenocarcinomas appeared in the groups with the highest cumulative exposure in both men (OR 3.0; 95 % CI 1.5–5.7) and women (OR 6.2; 95 % CI 2.0–19.7), whereas relative risks for squamous cell carcinomas were not significantly increased (OR 1.2; 95 % CI 0.8–1.8 and OR 1.5; 95 % CI 0.6–3.8 in men and women, respectively). However, in the group with highest probability of formaldehyde exposure, an elevated relative risk of squamous cell carcinomas was observed in men (OR 2.5; 95 % CI 0.6–10.1) and women (OR 3.5; 95 % CI 1.2–10.5). Formaldehyde exposure has also been studied in four case-control studies not included in the pooled analysis (Fig. 7.6) and was found to be associated with an increased risk of sinonasal cancer in two of them.
Exposure to formaldehyde. Estimated relative risks from case-control (CC) studies (Forest plot) for sinonasal cancer associated with occupational exposure, by main histological types. Diamonds represent the estimated ORs, horizontal lines represent the 95 % CIs, and the size of the gray squares indicates the relative size of the study population in each stratum. OR, odds ratio; 95 % CI, 95 % confidence interval
Textile Workers/Textile Dust
Data from the 12 case-control studies presented above and in Table 7.1 were analyzed according to the occupation and industry [18]. This pooled analysis detected an increased risk of sinonasal adenocarcinoma among women employed in the textile industry (OR 2.6; 95 % CI 1.0–6.6), and a high risk of squamous cell carcinoma for men involved in fiber preparation (OR 5.1; 95 % CI 1.3–19.2) or finishing of textile products (OR 3.0; 95 % CI 1.0–9.1).
The same dataset was also analyzed according to exposure to textile dust, which was considered a plausible causal agent [19]. The risk of adenocarcinoma was associated with cumulative exposure to textile dust only in women, with no clear dose-response relationship: the ORs were 1.7, 3.5, and 2.5 for low, medium, and high levels, respectively. No association with the cumulative level, probability, and duration of exposure to textile dust was found among men for both histological types or among women for squamous cell carcinoma. However, a high risk of squamous cell carcinoma (OR 6.6; 95 % CI 1.4–31.8) was observed among men who had been exposed to more than 0.5 mg/m3. Textile dust or textile work was also associated with elevated risks of sinonasal cancer in several other case-control studies (Fig. 7.7).
Exposure to textile dust. Estimated relative risks from case-control (CC) studies (Forest plot) for sinonasal cancer associated with occupational exposure, by main histological types. Diamonds represent the estimated ORs, horizontal lines represent the 95 % CIs, and the size of the gray squares indicates the relative size of the study population in each stratum. OR, odds ratio; 95 % CI, 95 % confidence interval
A possible role of exposure to formaldehyde has been proposed to explain the observed elevated risk in the textile industry, but in the pooled analysis, adjustment for formaldehyde exposure did not change markedly the ORs associated with textile dust [19]. The difference between men and women might be explained by exposure to different types of textile fibers. The role of cotton dust was postulated by Brinton et al. [35], who reported a high proportion of cases exposed to cotton. The nature of textile fibers (cotton, wool, synthetic fibers) was available in four studies in the pooled analysis, but when the data were combined, no specific effect of a particular type of textile was found [19].
Other Occupational Exposures
An increased risk of carcinomas of the paranasal sinuses and mastoid process was found in radium watch-dial painters, who ingested radium by “pointing” their brush with their lips. This excess risk was associated with internally deposited radium-226 [15]. There is also sufficient evidence that the manufacture of isopropyl alcohol by the strong-acid process causes sinonasal cancer. The evidence is inadequate to draw conclusions on the carcinogenicity of isopropyl alcohol, isopropyl oils, or isopropanol produced using other methods [63].
Other occupational exposures have been associated with the risk of sinonasal cancer, such as paints [42], adhesives [24], cutting oils [49, 50], and chlorophenols [33, 54, 55]. In the pooled analysis [19], an increased risk of squamous cell carcinoma was observed among men with a high cumulative exposure to asbestos (OR 1.6; 95 % CI 1.1–2.3). However, no significant association has been found in the few other case-control studies that have evaluated the risk associated with exposure to asbestos [21, 42], but the level of exposure and the histological type were not taken into account. Associations between exposure to arsenic (OR 5.2; 95 % CI 1.20–22.20) and sinonasal squamous cell carcinoma and between exposure to organic solvents and adenocarcinoma (OR 8.2; 95 % CI 4.32–15.72) have also recently been reported [38] and need to be confirmed.
A high risk of sinonasal cancer has been observed in many other occupations. The pooled analysis of 12 case-control studies highlights several associations [18]. Some results have reinforced the plausibility of associations reported in other studies (not included in the pooled analysis): a significantly elevated risk of sinonasal cancer has been observed in farmers, men employed in the food industry, food preservers, cooks, and vehicle drivers. The high risks reported in some studies for coal miners [79], construction [23, 27, 43], or metalworking [28, 47, 79] were not confirmed in the pooled analysis. However, two new associations emerged with respect to sinonasal squamous cell carcinomas: significant ORs were observed for hairdressers (OR 2.87; 95 % CI 1.03–8.02) and rubber workers (OR 3.17; 95 % CI 1.28–7.86).
Other Risk Factors
There is a causal relationship between tobacco smoking and the risk of cancer of the nasal cavity and the paranasal sinuses [80, 81]. One cohort study and nine case-control studies have examined the risk of tobacco smoking and sinonasal cancer. The association is consistently stronger for sinonasal squamous cell carcinomas than for adenocarcinomas [82]. With an average relative risk of 1.5–2.5, the association is significantly less strong than for many other tobacco-associated cancers, e.g., for lung cancer with an estimated relative risk of 15–30 [82].
No other nonoccupational risk factor has been identified for sinonasal cancer. In particular, with regard to biological agents classified as human carcinogens, nasal cavity and sinuses are not among the cancer sites for which there is sufficient or limited evidence in humans. Although Epstein-Barr virus (EBV) infection is associated with sinonasal lymphomas, no relation was reported with sinonasal carcinomas. Similarly, the detection of human papillomavirus (HPV) was reported in sinonasal cancer cases, but there is a lack of evidence from case-control studies to support these data [83, 84].
Summary and Conclusions
Occupational factors have a predominant role in the etiology of sinonasal cancer, and apart from these exposures, only tobacco smoking has been confirmed as a risk factor. Exposures to wood dust and leather dust are predominantly associated with adenocarcinomas, whereas increased risks for tobacco smoking were mainly found in squamous cell carcinomas. Epidemiological data do not allow determining whether other occupational exposures linked to sinonasal cancer are associated with specific histological types. In addition, no epidemiological studies are available differentiating histological subtypes, such as intestinal-type adenocarcinoma. The very high excess risks associated with wood dust exposure, together with the large number of exposed workers, mean that wood dust is a major cause of sinonasal cancer.
Exposure Characteristics
There is a range of exposures where causality to development of sinonasal cancer has been documented (see Section on Epidemiology and Occupational Risk Factors). This section summarizes and discusses exposure characteristics for commonly used substances evaluated by the International Agency for Research on Cancer (IARC) as being carcinogenic to humans and to which there is sufficient evidence for sinonasal cancer in humans [4]. The work-related substances are wood dust, nickel compounds and nickel metal, and “shoe and leather work” (leather dust). Hexavalent chromium is also included, although in the latest IARC evaluation, it is stated that “the epidemiological evidence remains suggestive but inconclusive regarding the effect of chromium VI on nasal and sinonasal cancers” [4]. In addition to these occupational exposures, tobacco smoking is associated with increased risk of sinonasal cancer [81].
The exposure characteristics for each substance are summarized in Table 7.3. Formaldehyde is not included as there is only limited epidemiological evidence that formaldehyde causes sinonasal cancer, as opposed to nasopharyngeal cancer where the association with formaldehyde exposure is well documented [4, 89] (see Section on Epidemiology and Occupational Risk Factors).
All substances, except for “shoe and leather work,” are prevalent exposures all around the world. In 2001–2003, approximately 3.6 million workers in the European Union alone were being exposed to wood dust on a regular basis; worldwide the numbers are hundreds of millions [2, 90]). Similarly, several million workers worldwide are exposed to airborne fumes, dusts, and mists containing nickel and nickel compounds; the same is true for exposure to chromium or its compounds [62]. Smoking is still very prevalent in most countries and is practiced by more than 1,000 million people around the world [80, 81, 88].
Wood Dust
Wood dust exposure is present in many industries; the typical high exposure industries or tasks are furniture industry, cabinetmaking, and joineries [2, 4] (see Section on Epidemiology and Occupational Risk Factors). The wood dust exposure levels in various industries in the past and more recently have been fairly well documented; it is known that dust levels above 5 mg/m3 were previously common, mainly in sanding operations and similar tasks, for example, during furniture and cabinet manufacturing. However, even today many subjects are exposed to levels above 5 mg/m3 [90, 91]. In epidemiological studies on wood dust exposure and sinonasal cancer, more exposure-response relations have been revealed, and now there is evidence in the literature that high exposure (>1–5 mg/m3) for several years may be required in order to develop sinonasal cancer [2, 38, 57, 85, 92] (see Section on Epidemiology and Occupational Risk Factors). Although no threshold value exists, it is likely that health effects at exposure levels below 1 mg/m3 are clearly less significant as opposed to higher exposure levels [92].
Chromium VI
Exposure to hexavalent chromium is prevalent in a range of industries and chromium compounds have been in widespread commercial use for more than 100 years. High exposure to chromium VI occurs during chromate production, chrome pigment manufacturing, chrome plating, spray painting, and during welding [4, 62].
IARC’s evaluations are based on the excess cases of sinonasal cancer found in workers in chromium and chromium pigment production and among chromium platers, whereas no consistent relationship has been seen among spray painters and welders (see Section on Epidemiology and Occupational Risk Factors). Airborne chromium VI levels above 1 mg/m3 have been found in earlier studies, but in general the exposure levels have decreased substantially to below 10 μg/m3 in the chromium production industry [4, 86]. No epidemiological studies on chromate VI and sinonasal cancer have reported exposure-response relationships, and there is no definitive knowledge of the duration and the intensity of the exposure needed to cause sinonasal cancer.
Nickel Compounds and Nickel Metal
Nickel compounds and nickel metal are used in many industries and have also been in widespread commercial use for more than 100 years. High exposure to airborne nickel occurs in nickel refining, nickel alloy production, welding, electroplating, grinding, and cutting operations [4, 62]. IARC’s evaluation is based on excess cases of sinonasal cancer found among workers in the nickel refining industry and employees in hydrometallurgy and electrolysis plants, whereas no consistent relation has been seen in other occupations, e.g., welders. Furthermore, IARC’s evaluation is based on exposure to nickel compounds like nickel sulfate and the combination of nickel sulfides and oxides [4, 62] (see Section on Epidemiology and Occupational Risk Factors). For example, airborne nickel levels above 1 mg/m3 have earlier been found during nickel refining and nickel alloy production. The exposure levels have decreased with time, but are still highly variable with measured levels between 4 and 800 μg/m3 in different industries and with different production methods [4]. The past concentration levels of individual nickel compounds are not known. A range of epidemiological studies included exposure-response analysis, but no clear exposure-response relationships have been revealed. There is no firm knowledge of the duration and the intensity of the exposure needed to cause sinonasal cancer.
Shoe and Leather Work
Working in the “shoe and leather work” industry is causally related to the development of sinonasal cancer. Excess risks have been observed among workers employed in boot and shoe manufacture and in boot and shoe repair [87]. Shoe and leather work involves a wide variety of different work procedures and exposure to many toxic substances, and in the IARC monograph published in 1981, the occupation “shoe and leather work” was stated as the causal agent. In the following year, an increased body of evidence in both case-control studies and cohort studies revealed leather dust to be causally related to sinonasal cancer in a dose-dependent manner, especially adenocarcinoma (see Section on Epidemiology and Occupational Risk Factors). Leather dust is now considered as a human carcinogen by IARC [4, 14], but there is no firm knowledge of the duration and the intensity of the exposure needed to cause sinonasal cancer.
Tobacco Smoking
Smoking is still very prevalent worldwide and has been a common lifestyle-related exposure for at least subgroups of individuals for several decades [80, 81, 88]. Several studies have analyzed exposure-response relations for sinonasal cancer in terms of intensity (cigarettes/day), duration, or pack-years, and most have revealed a positive exposure-response relationship. No clear threshold limit for intensity or duration has been identified. In general, the associations to cancer of the nose and paranasal sinuses were considerably lower than for wood dust exposure [4, 88].
IARC has also evaluated the effect of involuntary smoking, the type of tobacco smoke exposure related to exposure at work, on the development of sinonasal cancer, and the evaluation concluded that the literature was sparse and with conflicting results [4, 88].
Pathology
General
The WHO Classification of Tumours [6] lists a total of 63 primary tumor types occurring in the nasal cavity and paranasal sinuses, 12 of which are malignant epithelial types of tumor (Table 7.4). The other tumor categories are benign epithelial tumors, soft tissue tumors, tumors of the bone and cartilage, hematolymphoid tumors, neuroectodermal tumors, and germ cell tumors. In addition to a linkage to occupational exposure, some sinonasal tumors are associated with viruses [6]. The lymphoepithelial carcinoma is strongly associated with EBV, and HPV can be identified in some cases of squamous cell carcinomas [6].
The most common location of the sinonasal carcinomas is in the maxillary sinus (55–60 %), 19–35 % occur in the nasal cavity, 9–15 % in the ethmoid sinus, and only 1 % in the sphenoid and frontal sinuses [93, 94] (Fig. 7.1). A staging (T) classification for maxillary and ethmoid carcinomas has been adopted [95]. Occupational exposure is predominantly associated with squamous cell carcinomas and adenocarcinomas (Fig. 7.8) with these two tumor types having somewhat different etiologies as indicated by epidemiological studies [2, 4, 6] (see Section on Epidemiology and Occupational Risk Factors).
Two main histological types of sinonasal cancer. Squamous cell carcinoma (a) and adenocarcinoma (intestinal type) (b) are illustrated hematoxylin-eosin staining; 20× objective used
In several studies, squamous cell carcinomas have constituted approximately 35–70 % of the malignancies in the sinonasal region [6, 94, 96] (see Section on Epidemiology and Occupational Risk Factors). Squamous cell carcinoma of the vestibule is considered to be a carcinoma of the skin rather than carcinoma of the sinonasal mucous epithelium. Adenocarcinomas account for a variable proportion of sinonasal cancers, varying from 10 to 50 %, depending on the country [6] (see Section on Epidemiology and Occupational Risk Factors).
Squamous Cell Carcinoma
Squamous cell carcinomas can be subdivided into distinctive forms including keratinizing, nonkeratinizing, and adenosquamous types (Table 7.4) [6]. An example of a keratinizing squamous cell carcinoma is shown in Fig. 7.8a. The precursor lesions to sinonasal squamous cell carcinomas are poorly known. Sinonasal Schneiderian (inverted) papilloma appears to be a precursor lesion in about 10 % of the cases; the role of squamous metaplasia remains undetermined [6]. There have been no reports describing any specific associations between squamous cell carcinoma subtypes and particular exposures (see Section on Epidemiology and Occupational Risk Factors).
Intestinal-Type Adenocarcinoma
Adenocarcinomas are divided into two groups by WHO, namely, the intestinal-type adenocarcinomas (ITACs) (Figs. 7.8b and 7.9) and the sinonasal non-intestinal type of adenocarcinomas (non-ITACs) [6]. A considerable proportion, 40 % of the sinonasal ITACs, involves the ethmoid sinuses, with the nasal cavities being implicated in 27 % of the cases and the maxillary sinus in 20 % [97, 98]. The distinguishing feature of ITACs is reflected in the name, i.e., they display features of intestinal carcinomas (large intestine or small intestine) morphologically, immunohistochemically, and ultrastructurally. The epidemiological studies on the association between sinonasal cancer and wood dust exposure do not differentiate between adenocarcinoma subtypes. However, the pathology literature associates ITACs with wood dust exposure [6].
Sinonasal intestinal-type adenocarcinoma (ITAC) of colonic type (a) hematoxylin-eosin staining, with immunochemistry (b–d). Immunohistochemically ITACs are positive for various epithelial markers: positivity for CK20 (b), CK7 (c), and CDX-2 (d) is shown (20× objective used) (Courtesy of Prof. Ilmo Leivo, MD PhD, Dept. Pathology, University of Turku, Turku, Finland)
Two classifications for ITACs are in use (Table 7.5) [98, 99]. The categories within the classifications are compatible between classifications as shown in the Table 7.5, with the exception that there is no subdivision of mucinous carcinomas in the Barnes classification [6, 98]. In this article, the Barnes classification will be used. Immunohistochemistry for cytokeratin has been routinely used to identify the origin of a tumor; immunostaining for cytokeratin 20 is typically positive in the intestinal epithelium and carcinomas, while cytokeratin 7 is positive in tumors of the respiratory tract. ITACs are usually positive for cytokeratin 20 and less so for cytokeratin 7 (Fig. 7.9b, c). The CDX-2 homeobox gene plays a crucial role in the differentiation of the intestine. CDX-2 is commonly expressed in ITACs (Fig. 7.9d) [100–102].
Precursor lesions to ITACs are of special interest as they could represent a marker which could be used in the early detection and prevention of malignancies in exposed workers. This question has been addressed in three articles [103–105] to some extent. In a cytological study, cuboidal cell metaplasia and goblet cell hyperplasia were observed in wood dust-exposed workers [104]. Histological metaplastic changes have also been associated with wood dust exposure [105]. In a third study examining mucosal lesions adjacent to ITACs, metaplastic and mild dysplastic lesions were found adjacent to the tumors [103]. However, the changes were present whether the patients had been exposed to wood dust or not. Interestingly, in the two later studies, wood dust was associated with increased expression of p53 tumor suppressor protein in epithelial nonmalignant cells.
Non-intestinal-Type Adenocarcinoma
The first description on low-grade sinonasal adenocarcinomas emerged in a study published in early 1980s [106]. In that study, high-grade tumors were also included, and the article noted that 12 of the 27 high-grade tumors displayed a striking similarity to moderately differentiated colonic adenocarcinomas, with the remainder presumably not exhibiting this feature [106]. The current WHO classification (Table 7.4) recognizes sinonasal non-ITAC tumors as a separate entity which is further divided into low- and high-grade subtypes [5, 6].
The low-grade type is relatively distinctive with numerous fairly uniform small glands or acini arranged in a back-to-back or a coalescent pattern with little or no intervening stroma. The glands are lined by a single layer of various types of fairly bland cells or sometimes by a double layer where the second layer consists of basal/myoepithelial cells. The prognosis of the low-grade non-ITACs is generally good. The high-grade non-ITAC can be described as a high-grade adenocarcinoma with a predominately solid pattern of growth, although glandular or papillary patterns can be detected [6]. The differential diagnosis between the high-grade non-ITACs and other high-grade adenocarcinomas is challenging [107]. It has been proposed that they form a heterogeneous group of tumors of multiple unknown entities or variants of known entities [107]. The survival rate of subjects with high-grade non-ITACs is dismal; 3-year survival is a mere 20 %.
There is rather limited information available about the immunohistochemistry of non-ITAC tumors. The study of Franchi and coworkers [100] included four low-grade non-ITACs, which in contrast to ITACs did not stain with CDX2 or cytokeratin 20 but stained with cytokeratin 7. In a recent article, high-grade non-ITACS were shown to lack staining for CDX2 and, for the most part, also for cytokeratin 20, whereas cytokeratin 7 staining was relatively common [107].
As mentioned above the epidemiological studies do not differentiate between adenocarcinoma subtypes. In addition, non-ITACs are considered to be rarer than ITACs [107], although there are apparently no studies specifically reporting on the relative frequency of ITACs and non-ITACs. Thus, there is no direct information evaluating the association of non-ITACs to various exposures (see Section on Epidemiology and Occupational Risk Factors).
Summary and Conclusions
The sinonasal area is composed of the centrally located paired nasal cavities surrounded by paired paranasal sinuses (maxillary, frontal, ethmoidal, and sphenoidal). Sinonasal carcinomas are rare. The most important locations of the tumors associated with occupational exposures are the nasal cavity, maxillary sinus, and ethmoid sinus. The two histological types predominantly associated with occupational exposure are adenocarcinoma and squamous cell carcinoma. Squamous cell carcinomas have seven different subtypes; no association has been reported between occupational exposures and the presence of a particular subtype. Adenocarcinomas are divided into intestinal-type adenocarcinomas and non-intestinal-type adenocarcinomas, with some 40 % of the former located in ethmoidal sinuses. The striking feature of the sinonasal ITACs is their close resemblance to adenocarcinomas of the intestine, with similar positivity for various immunohistochemical markers. ITACs presumably represent the majority of sinonasal adenocarcinomas.
There is a strong epidemiological association between wood dust exposure and adenocarcinomas. There is, however, no direct epidemiological information about the association of different adenocarcinoma subtypes to wood dust exposure. In the pathology literature, ITACs are often considered as being associated with occupational exposure to wood dust.
Mechanisms of Carcinogenesis
Relatively little is known about the pathomechanisms involved in the development of sinonasal cancer. However, there is mechanistic information obtained from experimental settings as well as from human biomarker studies on toxicity, inflammatory effects, genotoxicity, and carcinogenicity of wood dust, wood extracts, or chemical constituents of wood. In addition, there are a few studies that have investigated wood dust-related sinonasal cancer in humans providing further molecular and mechanistic data [2, 4].
The mechanisms involved in cancer development have not been investigated to any significant extent for occupational exposures other than wood dust considered to be associated with an increased risk of sinonasal cancer, e.g., exposure to leather dust or textile dusts. However, somewhat more is known about other exposures such as tobacco smoke, nickel and chromium compounds, and formaldehyde, all with evidence for genotoxicity and mechanisms involved [4, 63, 81, 88, 108].
The primary focus of this section will be on reviewing and discussing the data available for cancer mechanisms likely to be involved in the sinonasal cancer related to wood dust exposure. A brief summary of some of the experimental and human evidence published is presented in Table 7.6
.
Toxicological Features of Wood Dust Exposure
The chemical composition of wood largely varies according to the species of tree. The wood species used in wood-related industries vary not only from region to region but also by type of product; both hardwoods (gymnosperms, i.e., conifers) and softwoods (angiosperms, i.e., deciduous trees) are widely used. Wood dust, which is generated in processing of wood, is a complex mixture of substances, composed mainly of cellulose (approximately 40–50 %), polyoses and lignin, and a large and variable number of compounds of lower relative molecular masses. The last set of compounds include nonpolar organic extractives (fatty acids, resin acids, waxes, alcohols, terpenes, sterols, steryl esters, and glycerides), polar extractives (tannins, flavonoids, quinones, and lignans), as well as water-soluble extractives. With regard to the inorganic compounds in wood, chromium compounds have been identified although they primarily appear to be present in wood treated with preservatives or stains [2, 4].
A number of biologically active compounds has been identified in both hardwood and softwood species. For example, substances with biological activity belonging to many organic groups have been characterized in wood. These include terpenes, phenols, tannins, flavonoids, quinones, lignans, and stilbenes; wood also contains some alkaloids and furocoumarins [2]. The various mechanisms through which wood dust may exert its biological activity are not well characterized but are likely to be complex [2, 4].
Some of the compounds identified in wood have been found to exert cellular toxicity (for instance, abeitic acid, plicatic acid) or mutagenicity (Δ3-carene, quercetin). Furthermore, quinones, present primarily in hardwood species but some also in softwood [2], are recognized as redox-active chemicals that can generate radical oxygen species (ROS) and, ultimately, evoke a toxic response [130]. Wood, nevertheless, also contains compounds that may counteract such toxic effects (e.g., flavonoids and phenolic compounds with antioxidant capacity) [2]. Further adding to the complexity, some compounds or groups of compounds found in wood may exhibit both types of activities, depending on the chemical structure or metabolism in human tissues. One such example is quercetin, as mentioned above, classified as one of the mutagenic compounds [2] but also as a flavonoid known to function as a dietary antioxidant [131].
An essential characteristic of wood dust, in common with many other exposures with a known or putative capacity to increase risk of sinonasal cancer (e.g., leather dust, tobacco smoking, textile dust, welding fumes containing nickel or chromium; see Sections on Epidemiology and Occupational Risk Factors and Exposure Characterization), is that, in addition to a multitude of various chemical substances, it also contains particulate matter [2]. In wood dust, concentrations and types of particles present in the dust generated largely depend on the type of wood being processed and the methods used in the processing (sawing, sanding, etc.) [2, 4].
Related to its complex nature, wood dust exposure may exert human toxicity at many levels, e.g., through affecting particle deposition in and clearance from the upper respiratory tract. There are many characteristics such as breathing patterns, airflow, and airway epithelium condition of which are known to influence particle deposition in the respiratory tract [4, 132, 133]. Furthermore, there are a multitude of various cellular and molecular mechanisms involved in particle-induced toxicity, including the capacity to evoke DNA damage due to the generation of radical oxygen species (primary genotoxicity) or as a consequence of the inflammatory response elicited (secondary genotoxicity), known or at least suspected to occur in humans [4, 132–134]. It is likely that several of those contribute to wood dust-related toxicity in the epithelia of the nose, sinuses, and other parts of the respiratory tract. It has been suggested that impaired clearance of wood dust leads to prolonged exposure of the upper respiratory epithelium [3, 4].
Finally, in occupational environments where wood is being processed, there may be exposure to other chemicals or agents, such as glues, lacquers, paints, solvents, formaldehyde, wood preservatives, and fungal spores [2, 4].
Animal Carcinogenicity Studies on Wood Dust
Studies with experimental animals exposed to wood dust have so far provided little clarification for processes involved in wood dust-related sinonasal carcinogenesis. The few published studies on rodents (rats or hamsters), conducted mainly in the 1980s and 1990s, utilized inhalation or intratracheal injection as the routes of exposure to investigate carcinogenicity of beech or oakwood dusts. The results obtained from such studies have largely been negative or inconclusive [2, 4], at least partially due to many shortcomings in design and reporting [2, 4]. In addition to testing wood dusts as such in the experiments, the mutagenic fraction of beech dust solvent extract has also been studied for skin cancer (exposure by skin application) in mice. Similarly to the carcinogenicity studies on wood dust, the results reported for beech solvent extracts were somewhat variable [2, 4].
A more recent study on rats investigated the carcinogenicity of oakwood dust administered by inhalation, and in addition to pure oakwood dust, the carcinogenic effects of dust from oakwood treated with preservatives or a chromium-containing stain were examined. The results obtained were, however, inconclusive to some extent [135].
In the most recent evaluation by IARC [4], the evidence for the carcinogenicity of wood dust in experimental animals remained inadequate as few studies additional to those evaluated in the earlier monograph [2] had been published in the interim.
DNA Damage Induced by Wood Dust In Vitro
DNA damage following exposure to wood dust has been investigated in a few genotoxicity studies, with some positive results reported. Early work pointed to mainly weak bacterial mutagenicity for solvent or water extracts of oak, ash, obeche, walnut, and limba wood (also particle board) [2]. Consistent mutagenicity in the Salmonella assay was observed for beech wood extract (reviewed in detail in [2]). Wood extracts have also been studied in some other experimental systems for their ability to damage DNA, with positive findings [2, 4].
Apart from wood extracts, also dusts from hardwood and softwood species have been studied for their ability to cause DNA damage. Fine dusts from six commonly used wood species, including beech, birch, oak, teak, pine, spruce, plus dust from oak-coated medium-density fiberboard (MDF), were studied for DNA damage in a human lung cell line in a widely used genotoxicity assay (the Comet assay) [109]. The study found that hardwood (beech, teak) and softwood (pine) dusts, plus the MDF dust, induced genotoxicity. Importantly, it was reported that the DNA damage observed was not secondary to the cytokine response [109], pointing to primary genotoxicity.
Inflammatory Response to Wood Dusts Exposure in Experimental Studies
Recent studies have indicated that exposure to wood dust, both hardwood and softwood dusts, has the capacity to trigger a proinflammatory process by modulating the expression of macrophage-derived cytokines and chemokines. A series of in vitro studies revealed that fine dusts from hardwood species (oak, beech, birch, and teak) and softwood species (pine and spruce) modulate inflammatory response in rat alveolar macrophages [110], in a mouse macrophage cell line [111, 112], and in a human lung cell line [109]. In these in vitro experiments, hardwoods and softwoods have induced the expression of several cytokines (e.g., TNF-α, IL-6, and IL-8) and chemokines [109–112], with some quantitative differences being observed between some of the species [111, 112]. It is likely that the induction of an inflammatory response by wood dusts involves at least in part mechanisms mediated by ROS; reactive nitrogen species are also known to be generated in the inflammatory process [109, 110, 136]. As mentioned above, the timing of DNA damage induction in human A549 lung cells by hardwood and softwood dusts indicates that inflammatory response is not necessary for genotoxicity of wood dust [109].
The inflammatory effects of wood dust in the lungs were further studied utilizing in vivo mouse models. Repeated intranasal instillation of fine dust (particle size of ≤5 μm for >99 % of the particles) from two hardwood species, oak and birch, induced the influx of inflammatory cells (macrophages, neutrophils, lymphocytes, and eosinophils) into the lungs of nonallergic mice [113]. An enhancement of lymphocytes and neutrophils was observed after oak dust exposure, whereas a greater infiltration of eosinophils followed exposure to birch dust. The infiltration of inflammatory cells was associated with an increased level of expression of several cytokines, chemokines, and chemokine receptors in the lung tissue. Overall, oak dust appeared to be a more potent inducer of these inflammatory mediators than birch dust [113]. Finally, findings from an allergic (ovalbumin sensitized) in vivo mouse model have indicated that repeated airway exposure to fine oak dust can modulate pulmonary inflammation (and also asthmatic response) [114].
Inflammation has also been postulated to play a role in the development of sinonasal cancer in humans [2, 120]. Recently, increased expression of COX-2, an enzyme involved in prostaglandin synthesis and upregulated by many inflammatory factors, was described in sinonasal adenocarcinoma [137]. COX-2 expression showed a significant association to occupational wood dust exposure, whereas tobacco smoking was not linked with COX-2 expression [137].
Genotoxicity in Wood Dust-Exposed Workers
There are a limited number of studies that have investigated genomic damage in workers occupationally exposed to wood dust. The level of DNA damage (DNA single-strand breaks) in peripheral blood lymphocytes was about twice as high among wooden furniture workers who were smokers, when compared to nonexposed smoking controls [115]. Further, the study also observed significant induction of DNA repair in the exposed workers, both smokers and nonsmokers, working in a wooden furniture plant in Poland [115]. Another study by the same group assessed DNA damage in white blood cells (WBC) from another group of workers from the same wooden furniture manufacture plant. Increased levels of DNA damage were detected by the Comet assay in WBC of these woodworkers, as compared to controls, in both smokers and nonsmokers [116]. The two studies indicated that the elevated DNA damage reflected the genotoxic effects of wood dust exposure; however, the possibility that they may have been at least partially related to other exposures present in the work environment of furniture making could not be totally ruled out [115, 116].
A more recent study observed significantly higher frequencies of micronuclei and other nuclear changes in buccal mucosa cells of furniture workers exposed to high concentrations of mixed hardwood and softwood dust in a woodworking shop, as compared to controls. Smokers had higher micronucleus frequencies in both groups, with the wood-dust-exposed smokers exhibiting the highest frequencies [117].
Genetic and Other Alterations in Human Sinonasal Cancer
Studies on the molecular mechanisms involved in human sinonasal cancer, even though somewhat limited in number due to the rare occurrence of the malignancy, demonstrate a variety of genetic and other molecular alterations in sinonasal tumors, as described in more detail in the following section (see also Section on Molecular Markers). Many of these studies have investigated sinonasal cancer cases with occupational exposure to wood dust. However, very few studies have investigated larger series of cancers and provided detailed data on the exposure characteristics [125, 127]. Some of the molecular alterations, the tumor suppressor gene TP53 mutations in particular, show association to wood dust exposure [127, 128]. In some studies, adenocarcinomas (typically ITACs) from cases occupationally exposed to wood or leather dust have been investigated, with genetic and other molecular alterations being reported [118, 119, 121–124, 126, 138] (see Section on Molecular Markers) for detail).
Other alterations include a reduction of mucociliary transport and neoplastic lesions (epithelial hyperplasia, metaplasia, and dysplasia) proposed to play a role in the development of wood dust-related sinonasal cancer [2, 4]. It is noteworthy that wood dust particulate matter, as well as the chemical constituents present in wood, is believed either to directly participate in such processes or to be able to enhance them [2, 4, 132].
There are also data suggesting that viral factors (HPV or EBV) and some host factors, such as nasal polyps, sinusitis, or rhinitis, may be involved in sinonasal tumorigenesis but the evidence and suggested contributions have remained open [2–4, 132].
Summary and Conclusions
Experimental in vitro and in vivo studies on wood dust have described a wide variety of adverse biological effects and molecular changes, including cytotoxicity, oxidative DNA damage, genotoxicity, inflammatory response, and increased cell proliferation. It is believed that particulates, chemical substances, and their combinations present in complex mixture exposures, such as wood dust exposure, are the primary players in evoking these harmful effects likely acting in concert in the biological and molecular pathways leading to development of sinonasal cancer.
There are also reports, although somewhat limited in number, pointing to the occurrence of wood dust-related genotoxic effects in exposed workers, in line with findings of the DNA damaging capacity of wood dusts as reported in various in vitro test systems. Studies carried out on human sinonasal cancer, perhaps not as plentiful as they could be if the cancer type were not so rare, have observed multiple genetic and other molecular alterations in the tumor tissue. These findings are also in good agreement with the experimental data and findings from exposed workers.
Collectively, the various sets of data point to a central role for genomic damage, in particular TP53 mutations, in the development of sinonasal cancer. The frequent occurrence of TP53 mutations fit well with data from other human cancers which involve regular, long term-exposure to carcinogens, including head and neck cancer. Inflammation is likely to also play a role in the carcinogenesis process. Much less is, however, known about how cancer susceptibility, other host-related factors, or viruses may contribute to tumorigenesis.
Finally, it appears justified to speculate that similar cancer mechanisms as described in the literature for wood dust-related sinonasal cancer may be involved, at least to some extent, in the sinonasal carcinogenesis associated with some other occupational exposures. There is, however, virtually no data available on mechanisms leading to cancer development in association with occupational exposures other than wood dust.
Molecular Markers
Literature on molecular markers in human sinonasal cancer is limited, as partially summarized and discussed in the previous section (see Section on Mechanisms of Carcinogenesis). Overall, the published findings have mainly been based on a relatively small number of cases, mostly involving adenocarcinomas. The studies published have, for example, described high frequencies of DNA copy number changes as detected by comparative genomic hybridization [119, 129, 139], while the mutation rates reported for the KRAS gene [123–126, 140–142] and the TP53 tumor suppressor gene [118, 122, 127, 143, 144] in general have been lower or variable. Furthermore, a few studies have indicated that epigenetic changes (mainly promoter hypermethylation of certain tumor suppressor genes) play a role in sinonasal cancer as in many other types of human cancer [118, 145].
TP53 and KRAS Gene Mutations in Human Sinonasal Cancer
Most of the studies exploring the tumor suppressor gene TP53 mutations, a hallmark genetic change in human cancer [146, 147] or investigating accumulation of the p53 protein in the cell have focused on intestinal-type adenocarcinomas, and there have been limited numbers of cases. In general, the accumulation of p53 often reflects a TP53 mutation, but other reasons for p53 accumulation are also known; furthermore, not all mutations induce nuclear accumulation of p53 [148, 149]. The results reported for sinonasal cancer indicate that p53 accumulation is a common feature in the adenocarcinomas, with immunopositivity ranging between 20 and 100 % [118, 122, 141, 142, 150, 151]. In the studies analyzing the TP53 mutations, a variable occurrence has been reported (18–60 %) [118, 122, 141, 143, 144]. TP53 gene mutations were investigated in a large series of sinonasal cancers collected in three European countries (Denmark, Finland, and France; n = 358 cases), with both adenocarcinoma and squamous cell carcinoma histological types being included [127]. All histological tumor diagnoses were reviewed in consensus by a pathology panel, and data on occupational exposure to wood dust were obtained by interview and assessed by industrial hygienists [127]. The study detected a significantly elevated risk of adenocarcinoma histology as opposed to squamous cell carcinoma among the wood dust exposed cases. Furthermore, an overall high frequency of TP53 mutations (77 %) was found among all sinonasal cancers. The risk of TP53 mutations was higher among the adenocarcinomas as compared to the squamous cell carcinomas, but there was no difference between ITACs (86 %, 76 of 88 studied) and non-ITACs (85 %, 29 of 34 studied) [127].
The multicenter study further found that TP53 mutations increased along with increased duration of occupational wood dust exposure, with a fivefold increased risk seen in association with ≥24 years of exposure (OR 5.1; 95 % CI 1.5–17.1), in comparison to nonexposed cases [127]. In addition, an elevated risk of mutation was significantly related to an average level of wood dust exposure of >2 mg/m3 (OR 3.6, 95 % CI 1.2–10.8) and to a cumulative level of exposure of 30 mg/m3 × years (OR 3.5, 95 % CI 1.2–10.7). Neither tobacco smoking nor formaldehyde exposure affected these findings significantly [127]. In a further investigation, some differences between the wood dust-exposed and the nonexposed cases in the TP53 mutation profiles were discovered (Fig. 7.10) [128].
Profile of tumor suppressor gene TP53 mutations in sinonasal cancer and in comparison to head and neck cancer. (a) Mutations presented by location (codon number in TP53 gene) in a series of sinonasal cancers studied in a European multicenter study by Holmila et al. [127] (top) as compared to similar data for head and neck cancers in IARC mutation database (IARC TP53 Mutation Database, version R16, 2012) (bottom). (b) Types of mutations detected in the multicenter study by Holmila et al. [128] (top) as compared to those included in the IARC mutation database (IARC TP53 Mutation Database, version R16, 2012) (bottom). The data for head and neck cancer from IARC database do not include sinonasal cancer cases. Numbers of cancer cases included in the analyses and the various classes of mutations are indicated
In a series of 44 sinonasal ITACs from Spain, mostly from cases occupationally exposed to wood dust, TP53 mutations were also commonly detected (41 %), and they were exclusively found in cases with occupational wood dust exposure [122]. From smokers, only 20 % exhibited TP53 mutation. The profile of mutations discovered in the study exhibited characteristics supporting wood dust-related etiology [122]. Based on the mutation profiles observed (50 % G to A transitions, almost exclusively detected in nonsmokers; all G to T transversions detected in smokers), the authors proposed that reactive nitrogen species generated via chronic inflammatory process contributed to the TP53 gene mutagenesis in the exposed cases [122].
Initially, also KRAS and HRAS mutations were reported to be relatively frequent in sinonasal cancer, with implications for histogenetic and prognostic significance [118, 123, 124, 140–142]. In the large multicenter study of Bornholdt and coworkers [125], the frequency of KRAS mutations in adenocarcinoma histology (13 %) was similar to that found in earlier studies. Furthermore, the KRAS mutations were found almost exclusively in adenocarcinomas (of which two were ITACs) [125]. The most common type of mutations was G to A substitution; this was also the case among the few wood dust exposed cases [125]. A case series of sinonasal cancers from Spain (57 squamous cell carcinomas and 58 ITACs) were examined for KRAS and BRAF gene mutations. From these, seven cases (12 %), all ITACs and woodworkers, were positive for KRAS mutations but no BRAF gene mutations were found [126].
Other Genetic Features
In addition to mutations found in the central cancer-related genes, chromosomal imbalances, loss of heterozygosity (i.e., loss of one of the two alleles or the target gene region due to genetic alterations), gene amplifications, as well as altered gene expression have been discovered in human sinonasal cancer (reviewed in [2, 4, 120]). The pattern of chromosomal abnormalities found in sinonasal adenocarcinomas appears to be different from that of the other tumors of the head and neck region but displays similarities with gastric and colonic adenocarcinomas [121]. On the other hand, DNA copy number analyses and microarray comparative genome hybridization in sinonasal squamous cell carcinoma have shown gene amplifications and similarities with genetic changes found in head and neck squamous cell carcinomas (HNSCC) [152, 153]. In ITACs, comparative genomic hybridization analysis conducted on a limited number of tumors suggests copy number gains and loss throughout the whole genome [120]. In a study reporting on a series of almost 100 ITACs from Spain, EGFR (epidermal growth factor receptor) gene copy number changes were detected in 46 % of the cases [138]. All cases were, nevertheless, negative for EGFR mutations, while 31 % were positive in immunohistochemistry for EGFR expression [138].
It is well known that even though environmental factors predominantly contribute to the development of most common cancers, heritable factors are also involved [154]. In addition to somatic alterations as reviewed above for sinonasal cancer, genetic susceptibility plays a role in tumorigenesis [155]. However, only very limited data are available regarding genetic susceptibility in sinonasal cancer. A study of 30 cases of ethmoidal ITAC and 79 noncancer controls suggested an overrepresentation of a certain CYP1A1 genotype (heterozygotes for codon 46 Thr/Asn) as well as of the combination of this genotype and the deletion (null) genotype of GSTM1 gene among ITAC cases [156].
Other Molecular and Cellular Changes
The molecular alterations reported for sinonasal cancer have included changes in protein expression as mentioned earlier (see Section on Pathology). Expression of Annexin A1, a member of the annexin family known to be implicated in a broad range of cellular processes, e.g., maintenance of the cytoskeleton, extracellular matrix integrity, tissue growth, and differentiation, was found to be frequently lost in all types of ITACs compared to nonmalignant tissue [157]. The expression of another member of the annexin family, Annexin A2, was also reduced in ITACs; however, this loss was restricted to the less differentiated histopathological types [157]. Another study examined 62 cases of ITACs (most with a history of employment in leather or wood industry) using tissue microarray [158]. Expression of p53 and p16 was the most common alteration observed in ITACs, with mucinous ITACs exhibiting a molecular profile distinct from that of non-mucinous ITACs [158]. Earlier, a difference in the expression pattern of the cell cycle regulators p21, p27, and p53 has been identified between adenocarcinomas and other tumor types of paranasal sinuses, especially the adenoid cystic carcinomas [152].
The expression of COX-2, an enzyme involved in inflammation, has been found to be associated with adenocarcinoma type of tumors, wood dust exposure, and nonsmoking [137]. In another study, EGFR expression was increased among ITAC type of tumors from workers exposed to wood dust [159]. Furthermore, profiling of gene expression in sinonasal adenocarcinomas has led to the identification of the two differentially expressed proteins LGALS4 and CLU [160].
Other types of changes include impaired mucociliary clearance and mucosal alterations that have consistently been reported in sinonasal cancer and associated with chronic wood dust exposure [2]. Mucosal alterations include dysplasia and metaplasia of the columnar epithelium and, to a lesser extent, changes in the squamous epithelium [2, 4, 104].
Summary and Conclusions
Sinonasal cancer exhibits an array of molecular changes, such as DNA copy number changes, allelic imbalance or loss of heterozygosity, gene amplifications, epigenetic changes, and altered gene expression, some of which it apparently shares with head and neck cancer. Mutations of the TP53 gene frequently occur in sinonasal cancer, and TP53 mutations have been associated with one of the main occupational risk factors, wood dust exposure. KRAS mutations also occur but are clearly less frequent compared to TP53 mutations. Changes in protein expression profile have also been reported. However, since a distinctive feature of sinonasal cancer is its rare occurrence, more data on molecular markers central to this cancer type are likely to accumulate in the future.
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Acknowledgements
We thank all our colleagues who participated in the research collaboration in connection with the EU 5 FW project WOODRISK (QLK-2000-00573) and afterwards. Dr. Ewen MacDonald, University of Eastern Finland, Kuopio, is thanked for language revision and Ms. Ritva Järnström, Finnish Institute of Occupational Health, Helsinki, for technical assistance.
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Husgafvel-Pursiainen, K. et al. (2014). Sinonasal Cancer. In: Anttila, S., Boffetta, P. (eds) Occupational Cancers. Springer, London. https://doi.org/10.1007/978-1-4471-2825-0_7
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