Department of Obstetrics and Gynecology University of Helsinki
Helsinki University Hospital
LICHEN SCLEROSUS AND LICHEN PLANUS IN WOMEN
INCIDENCE, RISK OF CANCER AND CAUSES OF DEATH
Pia Halonen
ACADEMIC DISSERTATION To be presented for public discussion
with the permission of the Faculty of Medicine of the University of Helsinki in the Seth Wichmann auditorium at the Helsinki University Hospital,
on the 11th of December 2020 at 12 o’clock.
Helsinki 2020
Docent Maija Jakobsson
Department of Obstetrics and Gynecology University of Helsinki and
Hyvinkää Hospital
Professor Oskari Heikinheimo
Department of Obstetrics and Gynecology University of Helsinki and
Helsinki University Hospital Professor Eero Pukkala Finnish Cancer Registry and Faculty of Social Sciences Tampere University Reviewed by
Docent Virpi Rantanen
Department of Obstetrics and Gynecology University of Turku and
Turku University Hospital Docent Riitta Luoto
Faculty of Medicine and Health Technology Tampere University
Official Opponent Docent Synnöve Staff
Department of Obstetrics and Gynecology Tampere University and
Tampere University Hospital
The Faculty of Medicine uses the Urkund system (plagiarism recognition) to examine all doctoral dissertations.
ISBN 978-951-51-6782-8 (paperback) ISBN 978-951-51-6783-5 (PDF) Unigrafia
Helsinki 2020
To my mother
Contents ... 4
Abstract ... 6
List of original publications ... 9
Abbreviations ... 10
Introduction ... 13
Review of the literature ... 14
Lichen sclerosus and lichen planus ... 14
Epidemiology ... 14
Etiology ... 17
Clinical Manifestations and diagnosis ... 20
Treatment ... 23
Follow-up... 24
Prognosis ... 25
Malignant potential ... 26
Summary ... 29
Cancers of women ... 32
Epidemiology ... 32
Cancers possibly associated with lichen in women ... 32
Mortality of women ... 37
Epidemiology ... 37
Risk determinants of mortality ... 38
Mortality of lichen patients ... 39
Aims of the study ... 41
Materials and methods ... 42
Subjects ... 42
Registers ... 42
Care register for health care ... 42
Finnish cancer registry ... 43
Cause-of-death register ... 43
Finnish population register ... 44
Statistical methods ... 44
Incidence of lichen ... 44
Cancer risk among women with lichen ... 45
Mortality among women with lichen... 45
Permissions ... 45
Results ... 46
Lichen sclerosus ... 46
Incidence (study I) ... 46
Cancer risk (study II) ... 48
Mortality (study I) ... 50
Lichen planus ... 52
Incidence (study III) ... 52
Cancer risk (study IV) ... 54
Mortality (study III) ... 55
Discussion ... 57
Incidence of lichen ... 57
Cancer risk ... 59
Mortality ... 61
Strengths and limitations ... 62
Future prospects ... 64
Conclusions... 65
Finnish summary ... 66
Acknowledgements ... 69
Appendices... 70
References ... 76
Original publications ... 90
Lichen sclerosus (LS) and lichen planus (LP) are dermatological diseases with similarities and differences. Both inflame the stratified squamous epithelial sites of the body, LS preferring the genitalia and LP the oral cavity and extragenital skin. The diseases are usually symptomatic – painful or itchy or both – and chronic with a capacity to cause complications and decrease the quality of life (QoL). LS diagnosis is usually straightforward, whereas that of LP can be tricky. Good symptomatic control is achieved with treatment, but the recommendations for long-term maintenance treatment and follow-up are ambiguous. Reports of cancers in LS and LP patients are scattered throughout the medical literature, but the associations remain unconfirmed. The effects of lichen on mortality are unknown.
The lack of large-scale epidemiological studies of LS and LP motivated this thesis. Finnish nationwide registries are the source of the data for the studies. Two cohorts – one with 7 800 women with LS and the other with 13 400 women with LP – were used to assess the incidence of lichen, associated cancer risk, and mortality following a lichen diagnosis made in the specialized health care.
LP was more common than LS in women: The incidence rates were 28 and 19/100 000 between 2003 and 2012. The incidence of LP stayed constant throughout the study period, but the incidence of LS rose from 14 in 2003 to 22/100 000 in 2012. Both lichens are mainly diagnosed in postmenopausal women with maximum incidence rates between 65 and 69 years for LP (64/100 000) and between 75 and 79 years for LS (53/100 000).
A small peak in incidence of LS was observed in 5- to 9-year-old girls.
Women with an LP diagnosis had an increased risk of cancers of the lip (standardized incidence ratio (SIR) 5.17, 95% confidence interval (CI) 3.06-8.16), tongue (SIR 12.4, 95% CI 9.45-16.0), oral cavity (SIR 7.97, 95% CI 6.79-9.24), larynx (SIR 3.47, 95% CI 1.13-8.10), esophagus (SIR 1.95, 95% CI 1.17-3.04), and vulva (SIR 1.99, 95% CI 1.18- 3.13). Women with LS were at increased risk of cancers of the vulva (SIR 33.6, 95% CI 28.9-38.6) and vagina (SIR 3.69, 95% CI 1.01-9.44), whereas the risk of cancer of the cervix was reduced (SIR 0.00, 95% CI 0.00-0.70). The observed cancer risks reflect the different predilection sites of the lichens and confirm the associations between LS and LP and cancers.
Women with an LS diagnosis had reduced mortality when compared to the population (standardized mortality ratio (SMR) 0.84, 95% CI 0.78-0.90). In contrast, the mortality of LP women was increased (SMR 1.07, 95% CI 1.02-1.11), with excess mortality from diseases of many organ systems (respiratory diseases (SMR 1.31, 95% CI 1.07-1.57), digestive diseases (SMR 1.39, 95% CI 1.09-1.75), infections (SMR 1.78, 95% CI 1.14- 2.64)), and cancers (mouth cancer (SMR 6.50, 95% CI 4.32-9.39), Hodgkin lymphoma
(SMR 6.37, 95% CI 1.83-17.2), non-Hodgkin lymphoma (SMR 1.68, 95% CI 1.11-2.44)).
A systemic inflammation involvement could, in theory, explain this finding.
Based on this thesis, an increased risk of cancers in women with LS and LP is confirmed.
Both lichens are fairly common diseases presenting to many different specialties.
Knowledge of the diseases’ effects outside the treating physician’s own specialty should be increased, especially for LP, given the increased patient mortality. Women with LP could benefit from care by multidisciplinary teams.
LIST OF ORIGINAL PUBLICATIONS
I. Halonen P, Jakobsson M, Heikinheimo O, Gissler M, Pukkala E. Incidence of lichen sclerosus and subsequent causes of death: a nationwide Finnish register study.
BJOG. 2020;127:814-819.
II. Halonen P, Jakobsson M, Heikinheimo O, Riska A, Gissler M, Pukkala E.
Lichen sclerosus and risk of cancer.
Int J Cancer. 2017;140: 1998-2002.
III. Halonen P, Jakobsson M, Heikinheimo O, Gissler M, Pukkala E. Incidence of lichen planus and subsequent mortality in Finnish women.
Acta Derm Venereol. 2020 Oct 28;100(17):adv00303.
doi: 10.2340/00015555-3664.
IV. Halonen P, Jakobsson M, Heikinheimo O, Riska A, Gissler M, Pukkala E.
Cancer risk of Lichen planus: A cohort study of 13,100 women in Finland.
Int J Cancer. 2018;142:18-22.
The original publications are reprinted with permission of the copyright holders. The publications are referred to in the text by their Roman numerals.
This thesis contains some previously unpublished data.
ABBREVIATIONS
AAOMP American Academy of Oral and Maxillofacial Pathology BCC basal cell carcinoma
BMI body mass index
BMZ basement membrane zone
BSSVD British Society for the Study of Vulval Disease CI confidence interval
DEJ dermoepidermal junction DHT dihydrotestosterone DIF direct immunofluorescence DNA deoxyribonucleic acid
dVIN differentiated vulvar intraepithelial neoplasia ECM1 extracellular matrix protein 1
ESP European Standard Population FCR Finnish Cancer Registry GP general practitioner HCV hepatitis C virus
HLA human leucocyte antigen HNC head and neck cancer HPV human papilloma virus
hrHPV high-risk human papilloma virus HS hidradenitis suppurativa
HSIL high-grade squamous intraepithelial lesion ICD International Classification of Diseases
ICD-O International Classification of Diseases for Oncology IRR incidence rate ratio
ISSVD International Society of the Study of Vulvovaginal Diseases JP Japanese Population
LE lupus erythematosus
LP lichen planus
LS lichen sclerosus
LV luottamusväli
MHC major histocompatibility complex mRNA messenger ribonucleic acid
NS not stated
OLL oral lichenoid lesion
OR odds ratio
PheWAS phenome-wide association study p16 tumor suppressor protein p16 p53 tumor suppressor protein p53 QoL quality of life
RCT randomized controlled trial
RR relative risk
SCC squamous cell carcinoma SIR standardized incidence ratio SLE systemic lupus erythematosus SMR standardized mortality ratio SNP single nucleotide polymorphism SPR standardized prevalence ratio SS Sjögren’s syndrome
T testosterone
Th1 T helper type 1
THL Finnish Institute for Health and Welfare USP United States Population
uVIN usual type vulvar intraepithelial neoplasia VIN vulvar intraepithelial neoplasia
VIN2 vulvar intraepithelial neoplasia grade 2 VVGS vulvo-vaginal-gingival syndrome WES whole-exome sequencing WHO World Health Organization
INTRODUCTION
According to medical dictionaries, the lichens are papule-forming skin diseases.
An archetype of the lichens is a disease called lichen planus (LP), first described in 1866 (1). Introduction of another lichen followed in 1875, nowadays known by the name of lichen sclerosus (LS) (2). Both are chronic, inflammatory diseases of the skin and mucous membranes. This thesis does not discuss other lichens (e.g., lichen nitidus, lichen amyloidosus, lichen simplex chronicus).
Little is known of the epidemiology, etiology, pathogenesis, and prognosis of LS or LP despite nearly 150 years of clinical experience and research. They have proven a difficult topic of study - patients are spread across different medical specialties and collecting enough material for research purposes is laborious.
Both LS and LP cause bothersome symptoms, complications, and a decrease in the quality of life. The current treatments relieve symptoms and prevent further complications but present no cure.
The first documented vulvar cancer in an LS patient is found in the aforementioned article written in 1875 by Weir (2). Hallopeau was the first to describe an oral cancer in an LP patient in 1910 (3), and many more reports of cancer associated with either lichen have followed. Still, to date, there is no consensus on the cancer risk or its magnitude. This raises concerns among patients and physicians, as well as ambiguous recommendations regarding the need of long-term follow-up of patients. Moreover, the mortality of lichen patients is yet an unstudied topic.
This thesis focuses on the health consequences of LS and LP. The included studies utilize the largest cohorts to date of women with LS and LP and focus on the incidence, cancer risk and mortality of lichen patients.
REVIEW OF THE LITERATURE
LICHEN SCLEROSUS AND LICHEN PLANUS
EPIDEMIOLOGY
Epidemiological studies of lichen sclerosus (LS) and lichen planus (LP) are few. Patients are attended to by different medical specialists – dermatologists, gynecologists, urologists, dentists, pediatricians, and general practitioners. Both LS and LP can be symptomless or symptoms may be embarrassing, leading to delays in getting care.
Lichen sclerosus
Lichen sclerosus (LS) is primarily a disease of the genital skin only. Exclusively extragenital skin manifestations occur only in 2-6% of cases (4-6), and the mucosa of the oral cavity may rarely be affected (7). Both genital and extragenital disease have been found in 11-18% of patients (4,5,8).
LS affects women more than men (4,9), and it can occur at any age (4,5,8). Most female patients develop symptoms just before or after menopause (4,8), and another smaller peak in incidence is reported in girls before menarche (8).
The crude incidence of LS estimated in two provinces of the Netherlands in 2006-2011 was 15 per 100 000 woman-years (10). Prevalence estimates vary between 2 and 14% depending on the study population (11-14). Table 1 presents a summary of the prevalence and incidence studies of LS.
Table 1. Studies of the prevalence and incidence of lichen sclerosus (LS).
Study Study design, study population, study period, country
Number of LS women
Rate
Leiboviz et al.
2000 (11)
Cross-sectional study, women residing in long-term care (n=96), NS, Israel
3 Prevalence 3%
Micheletti et al.
2000 (12)
Cross-sectional study, women attending a tertiary care vulvar clinic (n=3 350), 1986-1999, Italy
468 Prevalence 14%
Goldstein et al.
2005 (13)
Cross-sectional study, women attending a private gynecologic clinic (n=1 675), 1999-2003, USA
28 Prevalence 1.7%
Eberz et al.
2008 (14)
Cross-sectional study, women attending an annual routine gynecologic examination in a gynecologic private practice (n=2 800), 2007, Austria
200 Prevalence 7%
Bleeker et al.
2016 (10)
Retrospective cohort study, all LS diagnoses of women in a Pathological Registry, 1991-2011, Holland
3 038 Age-adjusted (ESP) incidence 12/100 000 woman-years
NS, not stated; ESP, European Standard Population
Lichen planus
Lichen planus (LP) characteristically affects many sites of the body. The oral cavity is the most common site and skin the second common one. Rare sites are the genitals, scalp, nails, larynx, pharynx, esophagus, external auditory meatus, and conjunctiva (15-22).
Oral LP is more often a disease of women, whereas cutaneous LP shows no gender predilection (23,24).
Oral LP is usually diagnosed in women in their 50s (25,26) and cutaneous about ten years earlier (27). LP is thought rare in children, but some studies report up to 10% of LP patients being under 15 years old (28,29).
A British study estimated the crude incidence of any LP in patients presenting to general practitioners in 1994-2003 to be 38 per 100 000 woman-years (30). A pooled global prevalence of oral LP of 1.55% in women was calculated in a recent meta-analysis (31), but the incidence estimates vary greatly due to heterogeneous study populations: 14-250 per 100 000 woman-years (32-34). The prevalence of cutaneous LP in women was 0.1% among screened Swedes (24), and the prevalence of vulvar LP was 3.7% in a patient material of a tertiary care gynecological clinic (12). The prevalence and incidence of other subtypes of LP are unknown. Table 2 presents a summary of the prevalence and incidence studies of LP.
Table 2. Studies of the prevalence and incidence of lichen planus (LP).
Study Study design, study population, study period, country
Number of women with LP
Rate
Any LP
Pannell et al. 2005 (30)
Cross-sectional study, women diagnosed with LP in a sentinel practice network (n=600 000 including women and men), 1994-2003, UK
940 Crude incidence 38/100 000 woman-years
Oral LP
Bhonsle et al. 1979 (32)
Cross-sectional study, women in several villages screened for oral diseases (n=5 374), NS, India
112 Crude incidence 280/100 000 woman-years
Nagao et al. 2005 (33)
Cross-sectional study, women in one town screened for oral diseases (n=4 316), 1995-1998, Japan
19 Age-adjusted incidence (JP) 188/100 000 woman-years
Laniosz et al. 2019 (34)
Cross-sectional study, women in one county diagnosed with oral LP (n=146 000, including men and women), 1986- 2010, USA
197 Age-adjusted (USP 2010) incidence 14.4/100 000 woman-years
Li et al. 2020 (31) Systematic review and meta-analysis, all population-based studies, 1965-2019
150 Global pooled prevalence 1.55%
Cutaneous LP Hellgren et al.
1970 (24)
Cross-sectional study, women in five counties screened for cutaneous LP (n=19 002), 1961-1963, Sweden
28 Prevalence 0.1%
Vulvar LP Micheletti et al.
2000 (12)
Retrospective case series, women attending a tertiary care vulvar clinic (n=3 350), 1986-1999, Italy
125 Prevalence 4%
Kennedy et al.
2008 (35)
Retrospective case series, women attending a tertiary care vulvar clinic (n=3 983), 1995-2003, USA
113 Prevalence 3%
Helgesen et al.
2010 (36)
Retrospective case series, women attending a tertiary care vulvar clinic (n=983), 2003-2009, Norway
158 Prevalence 6%
NS, not stated; JP, Japanese population; USP, US population
ETIOLOGY
The etiology of LS and LP is currently under speculation. Different etiological factors have been studied throughout the past decades, but none has been found play a key role in the etiology and pathogenesis of LS or LP. Most likely, the lichens arise through multifactorial mechanisms. Suggested factors in the etiology are presented next, and Table 3 elaborates them.
Immune dysregulation
Chronic inflammation of the stratified squamous epithelium lies at the core of both LS and LP. The initiating factors of the inflammation are currently unknown; however, a self-sustaining and self- amplifying pro-inflammatory process ensues. Both LS and LP are characterized by damaged epithelium and a lymphocyte-dominated inflammatory infiltrate (37-39). Details on genetic, epigenetic, molecular, and cellular level have been studied, but a unifying theory of the pathogenesis of the lichens is eagerly awaited.
Genetic susceptibility
Lichens run in some families, with up to 12% of affected family members with LS and 11% with LP (40- 42). Further support for genetic susceptibility to the diseases comes from associations to certain types of the human leucocyte antigens (HLA) in lichen patients (43-46). More recently, the sequencing of specified parts of the genomes of individuals has revealed certain common genetic variants among lichen patients (46,47). The clinical meaning of these findings is, for the present, unknown.
LS and LP have been described in patients of different ethnic groups without obvious predominance of one group over another. Most studies of LS report a great majority of women of European descent (5,8,48), and one recent study from New Zealand compared the ethnic origin of patients to census data and found an overrepresentation of European women (49). LP seems to show no ethnic predilection, but it was found more frequently in African American children in a small study from the USA (29).
Autoimmunity
The lichens fulfill many criteria that characterize autoimmune diseases (50): chronicity, female predominance, autoantibodies, autoreactive T-cells, lymphocytic infiltration of the target organ, effectiveness of immunosuppressant therapy, and comorbid autoimmune diseases (4,23,26,50-59).
Possible self-antigens are yet to be discovered.
Associated diseases and possible disease triggers
LS women, compared to controls, suffer more often from autoimmune thyroid diseases, alopecia areata, pernicious anemia, and morphea (58). LP women likewise have an increased frequency of systemic lupus erythematosus, Sjögren’s syndrome, vitiligo, alopecia areata, and thyroid diseases (58,59).
w of the literature Suggested contributing factors in the etiology and pathogenesis of lichen sclerosus (LS) and lichen planus (LP). ntributing factor Evidence in vulvar lichen sclerosus; ReferencesEvidence in lichen planus; References ic susceptibility sposing genetic variants 4 common gene variants in LS women in WES; Haefner et al. 2019 (47)6 common SNPs in LP patients in PheWAS of the MHC regi Liu et al. 2016 (46) itive family history9%; Higgins et al. 2012 (41) 12%; Sherman et al. 2010 (40)11%; Kofoed et al. 1985 (42) inance of certain HLA pesHLA-DQ7; Marren et al. 1995 (44) HLA-DR12; Gao et al. 2005 (43)HLA-A3, HLA-DR1, HLA-DQ5; Tziotzios et al. 2018 (73) toimmunity ntibodies targeting skin turesECM1 antibodies in 70% of LS women; Oyama et al. 2003 (53) BMZ antibodies in 30% of LS women; Howard et al. 2004 (54)
BMZ antibodies in 60% of vulvar LP patients; Cooper 2005 (55) BP180 antibodies in 17% of oral LP patients; Buijsrogge et al 2007 (74) mmune-type inflammatory milieuTh1 type proinflammatory cytokines dominant; Terlou et al. 2012 (39)Th1 type proinflammatory cytokines dominant in vulvar LP; Terlou et al. 2012 (39) tive T-cellsBP180 targeting T-cells in sera in 40% of LS women; Baldo et al. 2010 (56)BP180 targeting T-cells in sera in 40% of vulvar LP patients Baldo et al. 2010 (56) orbid autoimmune diseasesAlopecia areata, morphea, pernicious anemia, thyroid diseases more frequent in LS women; Cooper et al. 2008 (58)
Alopecia areata, SLE, SS, thyroid diseases, vitiligo more frequent in LP patients; Chung et al. (59) e chronicity80% cumulative relapse rate at 4 years; Renaud-Vilmer et al. 2004 (51)2% of patients with oral LP achieved remission in long-term follow-up; Carbone et al. 2009 (26) tiveness of immunosuppressing Topical steroid more effective than placebo; Bracco et al. 1993 (75)Topical steroid produces symptomatic control more often than placebo in oral LP patients; Lodi et al. 2020 (76) ale predominance Female:male ratio 10:1; Wallace 1971 (4)Prevalence of oral LP 2.2% in women and 1.6 % in men; Ax et al. 1987 (23) phocytic infiltrateCD4+ and CD8+ lymphocytes in dermal band; Farrell et al. 1999 (77)CD8+ lymphocytes intraepithelially, CD4+ lymphocytes at the DEJ in oral LP; Matthews et al. 1984 (78)
19
Triggers Altered hormonal statusDecreased serum DHT, androstenedione, increased free T in the sera of LS women; Friedrich et al. 1984 (79) LS OR 3 in women using anti-androgenic contraceptives; Gunterth et al. 2008 (80)
- Infections HCV- HCV OR 5 in LP patients; Shengyuan et al. 2009, Lodi et al. 2010 (68,69) HPV Conflicting results in review; Hald et al. 2018 (81)HPV DNA+ OR 5 in oral LP patients; Syrjänen et al. 2011 (82) Local trauma LS described in sites of various forms of local trauma; Todd et al. 1994 (71)Koebner phenomenon described in LP; Boyd et al. 1990 (70) Exposure to urinePrevalence of urinary incontinence increased in LS women; Berger et al. 2012 (83) Peristomal LS found in patients with urostomies; Al-Niaimi et al. 2013 (84) LS rarer in men circumcised at birth; Edmonds et al. 2012 (85)
- Other demographics Educational levelLS SPR 1.1 in patients with higher education; Virgili et al. 2017 (65) No effect; Sideri et al. 1989 (72)
- Income - LP RR 2 in patients with higher income; Chen et al. 2018 (86) Parity LS RR 3 in parous women; Sideri et al. 1989 (72)- ES, whole-exome sequencing; SNP, single nucleotide polymorphism; PheWAS, phenome-wide association study; MHC, major histocompatibility ex; HLA, human leucocyte antigen; ECM1, extracellular matrix protein 1; BMZ, basement membrane zone; BP180, a glycoprotein of basal ratinocytes; Th1, Thelpertype1; SLE, systemic lupuserythematosus; SS, Sjögren’ssyndrome; DEJ, dermoepidermaljunction; DHT, drotestosterone; T, testosterone; OR, odds ratio; HCV, hepatitis C virus; HPV, human papilloma virus; DNA, deoxyribonucleic acid; SPR, rdized prevalence ratio; RR, relative risk
LS and LP can coexist in a patient. Depending on whether LS and LP both manifest on genital skin or in different locations, an LS/LP overlap syndrome or their mere coexistence is diagnosed (60-62).
Similarly, LP and lupus erythematous have been reported to overlap or coexist (63,64).
Patients with LS had a higher body mass index (BMI) and were more hypertensive than controls in an Italian study (65). Dyslipidemia seems to be more common in LP patients than in controls in a meta- analysis (66), and patients may suffer from depression more frequently than the population according to a case-control study accompanied with a literature review (67). Hepatitis C virus is more frequent among LP patients than controls in certain geographical areas (68,69).
The Koebner phenomenon, a skin lesion appearing in the site of previous trauma, is described in both LS and LP and is considered a possible trigger in the development of the lichens (4,70,71). In support of koebnerization, high parity has been suggested to increase the risk of LS (72).
An association of LS with vulvar squamous cell carcinoma (SCC) is accepted, whereas the association of oral LP with oral SCC is debated over. These as well as other possible associations between the lichens and cancers are discussed further in later chapters of this thesis.
CLINICAL MANIFESTATIONS AND DIAGNOSIS
According to recent guidelines, LS is primarily a clinical diagnosis (87,88). Most diagnostic criteria for LP, however, include both clinical and histological findings (89-92).
Lichen sclerosus
More than 97% of women with LS are symptomatic, and the leading symptom is itch followed by pain (5,8,48). LS affects the skin of the vulva and perianus, and the classic clinical findings include white sclerotic or hypertrophic papules that, with time, coalesce to plaques. They are often accompanied with erythema, petechiae, edema, and fissuring. LS may cover the entire skin from the vulva to the anus in a typical ‘figure-of-eight’ pattern. Atrophy and scarring complicate long-standing LS and may lead to resorption of the labia minora or stenosis of the urethra, introitus, or perianus.
Extragenital LS most often affects the skin of the trunk or the extremities (4,5). LS of the oral mucosa, although rare, has most often been described on the labial or buccal mucosa (7).
The guidelines recommend histological confirmation on the following occasions: uncertain diagnosis, treatment resistance, or suspicion of (pre)malignancy (87,88). The classical histological picture includes three features: hydropic degeneration of the epidermal basal cells, dermal sclerosis, and a lymphocyte- dominated inflammatory infiltrate beneath the sclerotic belt (93).
Lichen planus
LP is a disease that manifests in different parts of the body and as different subtypes. A few of these subtypes dominate in a few locations, while the others represent only a minority. Table 4 shows the LP
Table 4. Different variants of lichen planus divided according to site of involvement and morphology of lesions. The most common variants are in italics.
Site Morphology
Skin Skin
External auditory meatus Actinic / (sub)tropicus
Extremities Annular
Genitals Atrophic
Nails Bullous
Scalp Classic / papulosquamous
Trunk Follicular
Guttate Hypertrophic Linear Pigmentosus Planopilaris
Mucous membrane Mucous membrane
Conjunctiva Atrophic
Esophagus Bullous
Genitals Erosive
Larynx Papular
Oral cavity Plaque
Pharynx Reticular
The most common subtypes are the reticular, erosive, and atrophic variants on the mucous membranes of the oral cavity (94-96). Reticular LP is identified by crisscrossing fine white lines, erosive LP by erosions and ulcerations, and atrophic LP by erythematous lesions usually accompanied by reticular lines.
The different subtypes often occur simultaneously, and they affect the oral cavity bilaterally and symmetrically (25,95,96). Multiple sites are typically involved, but the most frequent ones are the buccal mucosa, tongue, and gingiva (26,95,96). The reticular lesions are asymptomatic, but the atrophic and erosive lesions cause symptoms – usually pain (26,94,95).
The most common LP clinical subtype on the skin is the classic variant, which usually manifests as flat purple papules preferably on the extremities (97). Fine white lines can often be seen overlying the papules, which is a characteristic feature of LP called ‘Wickham’s striae’. The classic cutaneous LP lesions are itchy (27,97).
Hypertrophic cutaneous LP is more rare but mentioned here because of its differing clinical course compared to other cutaneous subtypes. It causes thick plaques most often in the lower legs, which are intensively itchy (98). The LP subtypes in the vulvar area match those of the oral and cutaneous LP, but the erosive subtype is most common (61,99). It presents as sharply demarcated erythema in the labia minora and the vestibulum, sometimes extending into the vagina. Vulvar erosive LP is highly symptomatic – usually painful.
LP’s ability to affect many sites of the body simultaneously or sequentially has been studied since Pelisse described a specific variant of erosive, multisite LP – the vulvo-vaginal-gingival syndrome (VVGS) - in
the 1980s (15). Oral LP patients have been studied the most: Simultaneous cutaneous LP lesions have been found in 8-20% of patients (26,100,101) and genital lesions in 3-57% of patients (26,61,101). Table 5 summarizes the studies on this topic.
Table 5. Patients with lichen planus (LP) and affected sites (%)
Number of patients Mouth (%) Skin (%) Genital (%) Esophagus (%) Larynx (%) Pharynx (%) Eye (%) Ear (%) Nail (%) Scalp (%) Urethra (%)
Any LP
Lewis et al. 1996 (102) 37 54 68 51 - - - - - - - -
Oral LP
Silverman et al. 1985 (100)
570 100 20 - - - - - - - - -
Eisen et al. 1999 (101) 584 100 16 15 1 - - 0.2 - 2 1 -
Belfiore et al. 2006 (61) 42 100 - 57 - - - - - - - -
Carbone et al. 2009 (26) 808 100 8 3 - - - - - - - -
Vulvar LP
Pelisse 1989 (15) 19 100 16 100 - - - - - - 5 -
Kirtschig et al. 2005 (103) 44 68 20 100 - - - - - - - -
Cooper et al. 2006 (52) 114 59 19 100 2 - - 1 1 4 8 -
Setterfield et al. 2006 (45) 40 100 40 100 15 3 5 15 5 13 20 3 Santegoets et al. 2010
(104)
95 57 8 100 - - - - - - 2 -
Conjunctival LP
Webber et al. 2012 (22) 9 100 56 100 56 - 11 100 22 - 44 11
Thorne et al. 2003 (105) 6 83 17 - - - - 100 - - - -
Otic LP
Sartori-Valinotti et al.
2013 (21)
19 58 26 58 21 - - 11 100 - - -
Esophageal LP
Katzka et al. 2010 (106) 25 76 12 52 100 - - - 4 4 - -
Fox et al. 2011 (107) 72 88 38 42 100 - - 1 - 3 7 -
The histological picture of classic cutaneous LP is evident: parakeratosis, acanthosis, hypergranulosis, hydropic degeneration of the basal layer, and a lymphocyte-dominated inflammatory infiltrate at the dermal-epidermal junction (108).
Mucosal LP lesions show the same histological findings, but there is more variation according to LP type, biopsy site, ongoing treatment, and disease activity (91,94,109). The proportion of diagnostic biopsies has been 77% at most in vulvar erosive LP (52,104,110). The optimal biopsy site is at the edge of the erosive lesion (109).
The diagnostic problems for oral LP have led to the development of sets of diagnostic criteria in 1978 (‘the World Health Organization (WHO) criteria’), 2003 (‘the modified WHO criteria’), and 2016 (the criteria of the American Academy of Oral and Maxillofacial Pathology) (89-91). The need to refine the criteria over the years has risen from the observation of great subjectivity in their interpretation (90).
Newer sets stress the need to exclude histological dysplasia and also other diseases mimicking LP in clinical or histological appearance. Perhaps the most important example of the latter is a disease group called the oral lichenoid lesions. They cause an LP-like lesion on the oral mucosa but have a specific cause – most often a medication or dental restorative material.
Diagnostics of erosive LP in the vulvar area is especially tricky, since both LS and LP share clinical and histological criteria and can coexist. Experts of the International Society of the Study of Vulvovaginal Diseases (ISSVD) and British Society for the Study of Vulval Disease (BSSVD) agreed upon diagnostic criteria for vulvar erosive LP in 2013 (109), but their nonspecificity recently led to the development of another set (111). An international study group suggested diagnostic criteria for esophageal LP in 2016 (20). Appendix 1 shows details of the sets of different diagnostic criteria for oral, vulvar, and esophageal LP.
TREATMENT
A few national or multinational guidelines exist for the treatment of LS and LP. Unfortunately, none of the currently available treatment is curative. Therefore, the aim of treatment is to reduce symptoms, reverse clinical signs, and prevent complications.
The guidelines do not give recommendations on whether symptomless LS should be treated. According to general consensus, asymptomatic oral LP does not need to be treated, but the disease must be monitored (112).
Lichen sclerosus
The recommended, first-line LS therapy is a topical ultra-potent corticosteroid ointment (clobetasol propionate 0.05%) (87,88), but its effect has only been proven in one randomized placebo-controlled trial (75).
An induction of treatment with clobetasol (a three-month regime: once daily with possible reduction of application frequency after the first month) produces a partial or complete symptomatic remission in 96- 100% and complete clinical remission in 23-54% of patients (8,51). The role of maintenance treatment is less studied, but most women will need it, according to clinical experience. Guidelines recommend commencing maintenance treatment at least after a relapse (87,88). Topical treatment with corticosteroids appears safe, with reversible local side effects (e.g., skin atrophy) in up to 4% of patients (48,51).
Few patients do not respond to topical corticosteroid preparations – 1.4% in an Australian study (48).
Topical calcineurin inhibitors (tacrolimus or pimecrolimus) are used in corticosteroid-resistant LS, but studies have shown their effect is inferior to that of clobetasol (113,114). Local steroid injections, local or systemic retinoids, and other immunomodulatory systemic preparations have also been used as an experimental treatment.
Lichen planus
The first-line therapy for most LP subtypes is topical corticosteroid preparations (92). Evidence concerning their effect and safety is surprisingly sparse.
A recent Cochrane review included only three placebo-controlled studies on the effect of topical corticosteroids on oral LP: topical corticosteroids achieved symptomatic control more often than placebo (76). Results stating the clinical response were inconsistent. The included studies reported almost exclusively local side effects only, but in both the active treatment and the placebo groups (76). Whether treatment reduces complications is unknown. Topical corticosteroids were found to be equal in effect to topical calcipotriol, systemic metronidazole, and systemic dapsone in a meta-analysis on treatments for cutaneous LP (115).
The frequency of application of the topical corticosteroids, the treatment duration, and the need for maintenance treatment are a matter of debate. No well-designed studies exist for the treatment of genital, or other rare forms of LP; therefore, the treatment regimens are extrapolated from those used in cutaneous LP and oral LP. Vulvar erosive LP is treated with topical clobetasol with a regimen similar to that in LS in clinical practice.
Short-term use of systemic corticosteroids is sometimes required if first-line therapy fails, especially in inducing remission (92). Intralesional corticosteroid injections may be of use in treatment-resistant lesions or ulcerations (92). The European guideline mentions topical calcineurin inhibitors, systemic retinoids (acitretin), and oral cyclosporine, among others, as second-line therapies, with no data of the superiority of one over another (92).
FOLLOW-UP
Given the chronicity of LS and LP and the potential for complications, long-term follow-up within the health care would seem appropriate. There is, however, no research investigating the potential benefits or harms of follow-up or the lack of it.
Lichen sclerosus
Guidelines recommend long-term follow-up within health care for patients with LS (87,88). Special health-care units responsible for vulvar conditions usually make the diagnosis and start treatment. The first follow-up visit occurs there at three months, after which patients are usually discharged into primary health care for yearly check-ups (87).
Furthermore, patients are encouraged to self-monitor their vulva. Patients are advised to contact medical assistance immediately if new symptoms occur and persist despite adequate treatment or if a lump or wound develops.
Little is known about whether the recommended follow-up occurs. According to two small studies, 30- 60% of the patients had subsequently visited their general practitioner for follow-up as advised (116,117), and only half of the women self-examined their vulva (117).
Lichen planus
The guidelines agree on the need to monitor patients with oral and vulvar LP long-term (92,112,118).
Additional self-monitoring of clinical signs is encouraged (112,118). The European guideline gives no direct recommendations regarding all other subtypes of LP (92). Patients with an LP subtype that is chronic will most likely benefit from long-term surveillance within health care.
PROGNOSIS
The lichens cause significant morbidity, but the effect on mortality is unknown.
Lichen sclerosus
LS runs a chronic course. A prospective study of 83 women with LS reported that the cumulative relapse rate after successful treatment was 50% at 16 months and 80% at four years (51).
Scarring is a known LS complication, present in 80% of women at diagnosis (8). Scarring is permanent, but only 3% of women adequately treated with topical corticosteroids developed it (48).
LS women suffer from a moderately impaired QoL (119). They report sexual dysfunction and sexual distress more often than controls (120). Adequate treatment with corticosteroids has been found to relieve, but not abolish, patients’ sexual distress (121).
Lichen planus
Classic cutaneous LP tends to self-limit within a year in 70% of patients, but later recurrences happen in half of the patients (27). The only known complication of classic cutaneous LP is postinflammatory hyperpigmentation, which persisted over five years in 26% of patients (27). Hypertrophic cutaneous LP shows marked chronicity and scarring potential, with an average duration of nine years and scarring in 63% of patients (122).
Mucosal LP usually runs a chronic course. Only 3-6% of patients achieved remission within a mean follow-up of 4-6 years in studies of oral LP and vulvar LP (26,52,100). Erosive LP has a potential to scar.
A study of 40 patients with VVGS reported that 90% had scarring of the vulva and/or vagina and 20%
of the oral cavity (45). Strictures were also rarely discovered in the esophagus, lacrimal duct, external auditory canal, urethra, pharynx, and larynx (45).
It seems inevitable that LP impacts patients’ QoL. A survey of women with LP of any type reported that the health-related QoL was moderately impaired (123). Erosive vulvar LP causes significant distress: 60%
of women report a moderate or high impact on their QoL and 70% reported sexual distress (124). Oral LP, especially the non-reticular subtypes, also seems to lower patients’ QoL (125,126).
MALIGNANT POTENTIAL
The association of LS and LP and cancer is a matter of debate. Squamous cell carcinoma (SCC) of the skin or mucous membranes is the malignancy generally associated with LS or LP. Details of the cascade of events leading to malignant transformation have yet to be elucidated. Chronic inflammation lies at the core, and it induces ongoing tissue damage and repair. Oxidative stress ensues, leading to the accumulation of epigenetic and genetic changes pre-requisite for carcinogenesis (127-133).
Several clinical, histological, and molecular markers have been studied to separate lichen patients with a greater risk of malignant transformation from those with low risk. None are yet used in routine clinical practice.
Lichen sclerosus
According to historical evidence, the risk of vulvar SCC in LS approximates 5% (134). Table 6 summarizes the studies with cancer as a primary outcome.
Table 6. Studies of lichen sclerosus (LS) with vulvar squamous cell carcinoma (SCC) as primary outcome.
Study Study design, source of data, study period, country
Number of LS women
Mean follow-up (months)
Number of vulvar SCCs
Absolute risk of vulvar SCC Carli et al.
1995 (135)
Prospective cohort study, tertiary care, 1982-1995, Italy
211 20 (median) 2 (previous cervical cancer in one patient, previous VIN2 in one patient)
0.9%
Cooper et al.
2004 (8)
Prospective cohort study, secondary and tertiary care, 10-year period, UK
253 66 6 2.4%
Bleeker et al.
2016 (10)
Retrospective cohort study, Pathology Registry, 1991- 2011, Holland
2 875 92 75 2.6%
Micheletti et al.
2016 (136)
Retrospective case series, tertiary care, 1981-2014, Italy
976 52 26 2.7%
Dell et al. 2018 (137)
Retrospective case series, tertiary care, 2004-2014, USA
275 NS 15 5.5%
Meani et al.
2019 (138)
Retrospective case series, tertiary care, 2012-2016, Australia
466 46 1 (previous
diagnosis of uVIN)
0.2%
VIN2, vulvar intraepithelial neoplasia grade 2; NS, not stated; uVIN, usual type vulvar intraepithelial
Association between LS and vulvar SCC has been confirmed; causality remains unresolved (139). Few attempts have been made to assess whether SCC arises from LS. Three studies have identified mutations in the tumor suppressor p53 gene, the most commonly mutated gene in human cancers, in LS and adjacent vulvar SCC. An identical mutation in the LS and SCC was found suggesting clonality (140-142).
Vulvar SCC is divided into two distinct subtypes: the human papilloma virus (HPV) positive and HPV negative types. LS is associated with the latter, the direct precursor of which is differentiated-type vulvar intraepithelial neoplasia (dVIN) (143). DVIN is often associated with LS (144), and a shared mutation in the p53 gene in a patient’s LS, dVIN and SCC suggests vulvar SCC developing from LS through dVIN (142).
Anecdotal evidence exists of the association of LS to other malignancies in the vulvar area. A recent Finnish study showed an increased risk of vulvar melanoma in patients with vulvar LS (145), and there are three case reports of a vulvar basal cell carcinoma in a patient with LS (146-148). Current literature includes a case report of multiple SCCs developing in a patient with extensive and treatment-resistant extragenital LS (149), but according to general consensus, extragenital disease is not associated with an increased cancer risk.
Wallace suggested that topical corticosteroid treatment might reduce the risk of malignant transformation in LS as early as in 1971 (4). Renaud-Vilmer et al. followed 83 women with LS for a median of 5 years in 2004 (51). A total of eight vulvar SCCs were seen, all in women who had not been treated or were inadequately treated with topical clobetasol, suggesting a protective role of topical therapy in cancer development. Lee et al. published results in 2015 of 507 women with LS followed for a mean of 5 years (48). The women were treated with different topical corticosteroids until remission followed by maintenance treatment. No vulvar premalignancies or malignancies developed in the compliant patient group, and 5% of the partially compliant group were diagnosed with vulvar intraepithelial neoplasia (VIN) or SCC.
Lichen planus
The cutaneous LP subtypes are not thought to be associated with malignancy (98,150). The hypertrophic variant may be an exception, with 38 reported cases of hypertrophic cutaneous LP and SCCs reported in literature in a review (98).
The association of mucosal LP and cancer is controversial. Oral SCC in oral LP patients is frequently reported in the literature. The main problem in defining their true association lies in the heterogeneity of the diagnostic criteria for the LP. Studies also report varying follow-up times and frequently have not specified exposures to carcinogenic factors (e.g., smoking, alcohol consumption). Even so, several systematic reviews and meta-analyses have been published recently, according to which the malignant transformation rate of oral LP was 0.4-1.4% (151-153).
The number of vulvar or esophageal SCCs reported in patients with LP is small, and the association uncertain. Table 7 summarizes the studies of LP and cancer.
Table 7. Studies of lichen planus (LP) with squamous cell carcinoma (SCC) as primary outcome.
Study Country
Study design, Source of data, Study period, Country
Number of patients
Mean follow-up (months)
Number of SCCs at location of LP
Absolute risk of SCC
Oral LP Giuliani et al.
2019 (151)
Systematic review and meta-analysis, 1978-2017
6 353 - 87 1.4%
Gonzalez-Moles et al. 2019 (152)
Systematic review and meta-analysis, 1929- 2018
25 848 - 360 1.4%
Idrees et al. 2020 (153)
Systematic review and meta-analysis, 2003-2020
12 838 - 56 0.4%
Vulvar LP Kirtschig et al.
2005 (103)
Retrospective case series, tertiary care, 1997-2000, UK
44 NS 1 2.3%
Cooper et al.
2006 (52)
Prospective cohort study, secondary and tertiary care, 5-year period, UK
114 72 1 0.9%
Kennedy et al.
2008 (35)
Retrospective case series, tertiary care, 1995-2003, USA
113 60 1 (previous
diagnosis of cervical cancer)
0.9%
Santegoets et al.
2010 (104)
Retrospective case series, tertiary care, 1995-2003, Holland
95 NS 2 2.1%
Esophageal LP Fox et al. 2011 (107)
Retrospective case series and a literature review, tertiary care 1994-2004, USA
72 NS 4 5.6%
Ravi et al. 2019 (154)
Retrospective case series, tertiary care, 1992-2017, USA
132 32 (median) 8 6.1%
NS, not stated
Few studies have assessed whether treatment affects the malignant potential of LP. Treatment with either topical or systemic corticosteroids and prophylactic antimycotics did not reduce the risk of cancer in two longitudinal studies of oral LP patients (155,156).
SUMMARY
Table 8 presents a summary of LS and LP, highlighting their similarities and differences.
