EPIDEMIOLOGY
An estimated 8.6 million new cancer diagnoses were made in the female population of the world in 2018, and 4.2 million women died because of cancer (157).
A reported 51% (i.e. 2.8 million) of the population consisted of females in Finland in 2017 (158). That year, 16 400 new cancer diagnoses emerged among women, and 6 000 women died from cancer (159).
Cancer was the third leading cause of death, but it was the first cause among working-aged women (15-65 years) (160). The three leading cancers in incidence and mortality were breast cancer, colorectal cancer, and lung cancer (159). The incidence rates of the leading cancers show an increasing trend in time (Figure 1).
Figure 1 Age-standardized (World Standard Population) incidence rates (per 100 000) of specific cancers 1953-2018 in Finland. (161)
CANCERS POSSIBLY ASSOCIATED WITH LICHEN IN WOMEN
Cancers possibly associated with lichen sclerosus (LS) and lichen planus (LP) include carcinomas of the stratified squamous epithelium: squamous cell carcinomas (SCC) of head and neck (HNC) (lip, tongue, oral cavity, pharynx, and larynx), esophagus, vulva, and skin. SCC is the most frequent histological subtype in all these locations with the exception of skin, and the subtypes other than SCC are not discussed further here.
Incidence
The incidence of squamous cell carcinoma (SCC) of the skin has risen in Finland since the 1950s (Figure 2), a trend also seen on a worldwide scale (162). The incidence of esophageal cancer shows a deep decline from the 1950s until the 1990s, when it stabilizes (Figure 2). The incidence of pharyngeal and tongue cancer, of the HNCs, has risen slightly in time. The incidence of other cancers associated with LS or LP has remained constant.
Figure 2 Age-standardized (World Standard Population) incidence (per 100 000 on logarithmic scale) of specific cancers 1953-2018 in Finland (161).
Risk factors
Human papillomaviruses (HPV) are DNA viruses that infect keratinocytes on skin and mucous membranes. More than 200 different types are identified to date, some of which, known as the ‘high-risk HPVs’ (hrHPV), have carcinogenic potential. HrHPVs are a causative factor – i.e., cancer samples were positive for HPV DNA as well as for mRNA of the oncoprotein E6 and/or p16 immunohistochemistry - in 21% of vulvar cancers, 19% of oropharyngeal cancers, 3% of oral cancers, and 1.5% of laryngeal cancers (163,164). HPV DNA has been detected in esophageal SCC, but, currently, the role of HPVs in the etiology of this cancer seems unlikely (165), whereas cutaneotropic HPVs may be involved in the development of skin SCC (166,167).
Tobacco smoking and alcohol consumption are known risk factors for cancers of the oral cavity, tongue, pharynx, larynx, and esophagus (168,169). Moreover, smoking and alcohol pose a synergist effect and an increasing dosage gives rise to increasing risk (168,169). Newer studies have especially associated these risk factors with the HPV negative head and neck cancers and found no association with the HPV positive cancers (170). Smoking and alcohol consumption also increase the risk of SCC of the skin, but they seem not to affect the risk of vulvar cancer (171-173).
There are a few premalignant conditions of the squamous epithelium that may progress to a SCC. Within the oral cavity, a group of ‘oral potentially premalignant disorders’ include, e.g., leukoplakia and erythroplakia (174). Leukoplakia, a white lesion on the oral mucosa that cannot be attributed to any disease, carries an annual malignant transformation rate of 1.6%, whereas erythroplakia, a red lesion that cannot be attributed to any disease, has an annual transformation rate of 2.7% (174). On skin, actinic keratosis and Bowen’s disease are premalignant conditions with low transformation rates (175,176).
Different grades of dysplasia or intraepithelial neoplasia with malignant potential are histologically diagnosed within the oral mucosa, larynx, esophagus, and vulva. The extent of dysplastic cells within the epithelium defines the grade of the dysplasia (mild: only the lower third; moderate: lower two thirds;
severe: more than the lower two thirds), and an increase in the grade gives rise to an increase in cancer risk (174,177,178).
Within the vulvar area, moderate and severe dysplastic lesions are currently joined under the term high-grade squamous intraepithelial lesion (HSIL), and the lesion is associated with persistent hrHPV infection. An HPV-unrelated precursor lesion in the vulvar area is also accepted – dVIN – characterized by atypia limited only to the basal layer of the epithelium. The etiology, histology, and clinical behavior of the two precursors differs markedly. The malignant progression rate of vulvar HSIL approximates 6%, whereas that of dVIN is 33% (179).
The development of SCC through a differentiated type of dysplasia is also suggested in the oral cavity, pharynx, larynx, and esophagus (180-182), but further studies are needed for these theories to be universally accepted. Additionally, a study described the histological precursors adjacent to skin SCCs and found the majority them to be actinic keratoses with atypia limited to the basal layer only (183).
Whether differentiated dysplasia is accepted as a precursor lesion in the development of SCCs of the skin and mucous membranes also outside the vulvar area remains to be seen.
DVIN is the only precursor lesion, which has been linked to LS in the genital area. LS was associated with dVIN in 3 of 12 cases of dVIN in an American study (144). According to a current hypothesis, HPV-negative vulvar SCC develops from LS through dVIN (143). Preliminary confirmation of this theory comes from small studies showing clonality of adjacent LS, dVIN and SCC (140-142). LP has not been shown to be associated with any of the precursors.
Immunosuppression increases the risk of head and neck, vulvar, and non-melanoma skin cancer (184).
Older age associates with increased risks of HNC, vulvar SCC, and skin SCC (185-187). Other risk factors for HNCs include poor oral health and higher intake of red and processed meat, whereas higher consumption of fruit and vegetables serves as a protective factor (188,189). Risk factors of vulvar cancer are obesity, early menopause, and a past diagnosis of cervical high-grade intraepithelial neoplasia (173).
The risk factors for SCC of the skin are exposure to UV radiation and fair skin color (190).
Some occupations affect workers’ risk of cancer either by directly exposing them to carcinogenic substances or by associating with certain lifestyle factors, such as with higher consumption of alcohol or more frequent smoking. A few studies estimate the risk of cancers of the head and neck, esophagus, skin, and vulva according to occupational categories. Some occupations were associated with increased and others with decreased risk of the cancers in question in the Nordic Occupational Cancer Study covering
(Table 9) (191). The likely explanation is the differing of lifestyle factors, whereas the direct exposures seem to be of little consequence.
Table 9. Occupations with increased or decreased risk of specific cancers in women in Finland within the Nordic Occupational Cancer study (191).
Cancer site Occupation with increased risk Occupation with decreased risk
Lip - Waiters
Figure 3 shows differences in cancer incidences in different regions within a country and between the Nordic countries. The differences are explained by geographical differences in risk factors.
Figure 3 Age-standardized (World Standard Population) incidence of specific cancers (per 100 000) 2008-2015 (192).