Studies on the cancer risk of LS and LP range from case reports to meta-analyses. Examples of the latter are those of the associations of LS with vulvar SCC and of oral LP with oral SCC (139,151-153).
Regarding other cancers reported in lichen patients, the association debate continues. Chronic inflammation is presently thought to be the driver of malignant transformation in LS and LP.
This thesis found a 34-fold increase in the risk of vulvar cancer in women with LS. The absolute excess risk of vulvar cancer increased with age: from 2 cases per 1 000 women per year in the youngest to 5 in the oldest age groups. The risk of vulvar SCC was 40-fold compared to the population. One previous study has calculated the SIR for vulvar SCC in LS women as 317 (95% CI 36-1146), but it included only 211 women with LS and 2 SCCs with a mean follow-up of 1.7 years (135).
The absolute risk of vulvar SCC in this thesis was 2.1%, in line with other studies (8,10,135,137,138). The absolute risks are not directly comparable, because the studied populations and follow-up times differ.
The absolute risk varies most, from 0.2 to 5.5%, in the smaller studies with 211-275 LS patients, but the absolute risks were 2.6 and 2.7% in Bleeker et al.’s study with 2 875 women and in Micheletti et al.’s study with 976 women (8,10,135,137,138). A 5% risk of vulvar SCC in women with LS was accepted before the widespread use of topical corticosteroids (134), and since subsequent studies concur, an upper limit of 5% is still cited by most recent research.
The SIRs for histological subtypes of vulvar cancer other than SCC were also increased: four for BCC and four for melanoma. The SIR for vulvar Paget disease, an intraepidermal malignancy, was 33. Vulvar BCC, melanoma, and Paget disease are generally rare malignancies, and their small number in our study complicates drawing definite conclusions. These malignancies may be found more frequently in LS
patients than in women not suffering from a gynecological condition, since the follow-up of LS patients is advised by guidelines.
An increased risk for vulvar melanoma in LS patients was suggested by a recent Finnish study that identified three melanomas in LS patients with a relative risk of 341 (145). The melanoma and LS diagnosis were simultaneous in the study in question, whereas the cancer diagnosis follows the LS diagnosis in our study, making comparisons between studies difficult. BCC of the vulva in a patient with LS has been reported only three times in the literature (146-148).
Only one previous report exists of a patient with LS and vulvar Paget disease (215). Extramammary Paget disease of the vulva may present with a variable clinical picture; it could, therefore, be clinically misdiagnosed as LS. This may explain the large number of Paget disease diagnoses following LS diagnoses by less than a year in our cohort. However, three Paget diseases were diagnosed over five years after the LS diagnosis (SIR 16), suggesting an actual association between the two conditions.
Why LS prefers women’s vulvar and perianal skin is not fully understood. The genitalia skin (from the mons pubis to the perianus) is constantly exposed to irritants – especially urine - in an occlusive manner.
Indeed, women with LS report urinary incontinence more often than the population (83).
Further support for the role of urine in the pathogenesis comes from studies on male LS. The male genitalia, due to obvious anatomical differences, are not in contact with urine in a similar fashion, which could explain the lower incidence of LS in men. Moreover, perianal involvement in genital disease is rare in men, and circumcision seems to protect from the development of the disease altogether (85).
Additionally, a case series of 11 patients with urostomies and peristomal LS suggests that some urine component may predispose the skin to the development of LS (84). However, local trauma – be it from urine or some other factor - may be the trigger or contributor in the pathogenesis of LS (the Koebner phenomenon).
An unexpected four-fold increase in the risk of vaginal cancer was seen in this thesis, even though LS does not affect the vaginal mucosa with the exception of a prolapse (216,217). On the contrary, the risk of cervical cancer was reduced in women with LS. LS causes adverse effects on sexuality, and patients may therefore be less exposed to the HPVs, causative factors of cervical cancer. LS patients may also be screened more frequently for cervical abnormalities because they suffer from a gynecological disease with regular check-ups. Lastly, smoking is a risk factor for cervical cancer, and LS women probably smoke less than the general population, as their risk of lung cancer is reduced.
LS sometimes manifests on the skin outside the genitalia and on oral mucosa (4,7). The risks of cancers in these locations equaled that of the population, which is in accordance with the literature, with only one reported case of multiple skin SCCs developing in a woman with multisite extragenital LS (149).
The risks among LP women for cancers of the lip, oral cavity and tongue were 5-, 8-, and 12-fold compared to the population. Two studies have previously calculated the SIRs for oral SCC in women with oral LP: 27 (95% CI 11-65) and 100 (95% CI 40-206) (155,156).
Increased risks of cancers in other locations affected by LP were discovered: a two-fold risk of esophageal
and vulva in patients with LP have been described in the literature, but their association is controversial due to the scarcity of cases and difficulties in the LP diagnostics (36,52,103,104,107,154).
Other locations affected by LP did not show increases in cancer risk (vagina, pharynx, skin). The literature does not describe them, either, with the exception of the hypertrophic variant of cutaneous LP. A literature review identified 38 cases of hypertrophic LP and simultaneous skin cancers, suggesting an association (98).
An important clinical question is whether treatment affects the cancer risk of LS and LP patients.
Concerns of an increased risk of cancer in patients using immunosuppressive medication have risen from studies of increased incidence of posttransplant malignancies in solid organ transplant recipients (218).
However, since chronic inflammation is thought to drive the malignant transformation in LS and LP, reducing the intensity of the inflammation with immunosuppressive medications could, theoretically, lower the risk of cancer.
Two studies have addressed this issue in LS. The first reported on 83 women with vulvar LS who were treated with topical clobetasol and followed for a mean of five years (51). All eight patients who developed a vulvar SCC had been inadequately treated. The second study reported on 507 women who were treated with topical corticosteroids of different potencies and followed for a mean of five years (48).
A total of seven women were diagnosed with a VIN or vulvar SCC, all in the non-compliant group. Thus, the lowering of the cancer risk with adequate treatment is suggested in vulvar LS.
Two studies mention the effect of treatment on the cancer risk in LP patients. The SIR for oral SCC did not differ significantly in a study of 402 patients with oral LP followed for a mean of five years between the groups of patients treated and not treated with topical or systemic corticosteroids (SIR 42 and 48, respectively) (155). The effect of topical therapy on the cancer risk in the other study of 327 patients with oral LP followed for 7 years was estimated with the incidence rate ratio (IRR), which was found non-significant between the groups treated and not treated (IRR 0.71, 95% CI 0.13-3.80) (156). More studies are required for this topic in both LS and LP until a consensus can be reached.
MORTALITY
No previous studies exist that investigated the causes of death or mortality of LS patients. The causes of death in the 1980s of 50 LP patients were compared to equal amounts of psoriasis patients and the population (203). Cancers of the gastrointestinal tract and bladder and malignant hemopathies (three acute myeloic leukemias and one myelosarcoma) as causes of death were more frequent among LP patients than in the other groups. The small sample size limits the interpretation of this result.
This thesis found the overall mortality of women with LS decreased, even considering the increase in mortality from vulvar cancer. Compared to the population, LS women die less often of circulatory diseases, dementing diseases, lung cancer, and alcohol-related causes, all of which are strongly affected by lifestyle factors. It is possible that a diagnosis or follow-up of a chronic disease induces healthy lifestyle choices in patients, or perhaps a healthier lifestyle predisposes women to LS.
The all-cause mortality of women with LP was increased because of increases in mortality from infections, respiratory diseases, and diseases of the digestive system. Additionally, the risk of death from cancers of the mouth and pharynx and non-Hodgkin and Hodgkin lymphomas was increased.
Some chronic inflammatory diseases, e.g., rheumatoid arthritis and SLE, are known to increase the risks of cancer in the organs in which they cause local inflammation (219,220). They may also increase the risk of hematological malignancies by means of systemic inflammation. Another skin condition, psoriasis, is characterized by local, but also systemic inflammation (221), and it has been linked to an increased risk of skin SCC, BCC, and non-Hodgkin lymphoma (222). This thesis found that the cancer risks of LPs target organs were increased; in addition, the mortality from lymphomas was increased, suggesting both local and systemic components in the inflammation. This hypothesis, however, needs further study.