Opinion
EDITORIAL
Reduced Risk of Squamous Cell Carcinoma With Adequate Treatment of Vulvar Lichen Sclerosus Susan M. Cooper, MD, FRCP; Nina Madnani, MD, DVD; Lynnette Margesson, MD, FRCPC
In this issue, Lee and colleagues1 present the results of the largest prospective clinical cohort study to date concerning 507 women with vulvar lichen sclerosus (VLS). The authors present evidence that poor compliance with topical corticosteroid (TCS) treatment predisposes patients to the development of Related article vulvar cancer and scarring. They propose that initial treatment regimens should be selected using a variety of corticosteroid potencies based on the severity of signs at presentation. They also propose that maintenance treatment for VLS should be the norm, increasing or decreasing the potency of treatment as necessary. The authors recommend life-long specialist follow-up. Development of vulvar skin cancer is a feared complication of VLS, but the exact risk of malignant transformation is uncertain. In studies described before the widespread introduction of superpotent corticosteroids for VLS treatment following the article by Dalziel et al in 1991,2 estimates of the development of squamous cell carcinoma were between 3% and 5%.3-5 In the poststeroid era, the second largest study from England, reported by one of us,6 estimated a risk of 2.4%; however, this risk increases to 4.0% if vulvar intraepithelial neoplasia (VIN) is included. The issue is complicated because previous studies3-5 did not include cases of VIN, and furthermore, the changes in classification of VIN mean that earlier studies may have included some cases of VIN with low potential for invasive squamous cell carcinoma. For years vulvologists have suspected that poor compliance with treatment might increase the risk of developing malignant neoplasms but have lacked proof because studies so far have lacked sufficient power to detect this difference. In the current study, Lee et al1 followed up 507 patients, tailoring their treatment to the clinical response, and assessed patients as being fully or partially compliant based on whether they self-reported that they followed instructions all or most of the time (fully compliant) or some, little, or none of the time (partially compliant). There was a statistically significant association between the risk of developing vulvar malignant neoplasms in the compliant group (357 [0%] women) vs the partially compliant group (150 [4.7%] women) (P < .001). Malignant neoplasms included 4 differentiated VIN and 3 invasive squamous cell carcinomas; however, differentiated VIN has a high potential to have invasive cells develop and therefore it is appropriate to include these cases. This article is an important contribution to our knowledge, providing the first evidence in women of the association between malignant neoplasms and poor compliance with treatment. This information will allow us to better inform our patients and encourage those who find it difficult to comply for various reasons.
The authors used self-reported compliance, with planned treatment as their only measure of compliance with TCS treatment. Compliance with oral medications is usually overestimated, with only one-sixth of patients who believe themselves to be compliant actually being fully compliant.7 Compliance with topical medications tends to be even lower than with oral treatments8 and decreases over time.9 Problems with using only 1 patient-reported measure include patients reporting what their physicians want to hear, forgetting missed treatments, and being overly optimistic about their compliance. In addition, compliance may vary during several years of treatment, decreasing when women forget about their asymptomatic disease or when important life events take over. Different health beliefs in some cultures can still be a barrier to compliance. Fear about perceived dangers of TCSs is still common and is not helped by package inserts that exhort patients to use TCSs for a short duration only and not to apply to mucous membranes. Furthermore, advice from dispensing pharmacists to use a product sparingly may contribute to anxieties. Elderly patients often have difficulty reaching the involved area. There are other ways of assessing compliance, such as recording the amount of corticosteroid used (by monitoring weight of tubes and prescriptions issued) or using diary charts and electronic capping of prescription containers. These measures may be appropriate for future studies. In this article, the reasons for poor compliance are not addressed but present a potentially fruitful area for future study. In the study by Lee et al,1 cohort treatment was tailored to the severity of disease, using the presence or absence and degree of hyperkeratosis as the principal marker of severity. The most severe cases with extensive hyperkeratosis were treated twice daily with a superpotent TCS and less severe cases with a reducedpotency TCS for the initial treatment period. This use is in contrast to the recommendations of guidelines.10,11 Starting with a superpotent corticosteroid has been advocated for all patients either as an initial 3-month once-daily regimen or a tapered regimen for 3 months. Signs at presentation vary considerably, with some women displaying severe widespread genital pallor, hyperkeratosis, fissures, and erosions whereas others show subtle pallor; there are yet others who are asymptomatic. Hyperkeratosis alone may not be a sufficient marker of active disease because ecchymoses and erosions may also be important. Tailoring treatment to the severity of the disease makes sense because in other inflammatory diseases, such as atopic eczema, dermatologists routinely tailor the potency of the corticosteroid used to the severity of the disease. Some patients in the study by Lee et al1 required more than 5 months of continuous treatment to control their symptoms. Could using a lesser potency of corticosteroid
jamadermatology.com
(Reprinted) JAMA Dermatology Published online June 12, 2015
Copyright 2015 American Medical Association. All rights reserved.
Downloaded From: http://archderm.jamanetwork.com/ by a Universite Laval User on 07/09/2015
E1
Opinion Editorial
lengthen the time it takes for the condition of the genital skin to improve? Introducing severity assessments and using varied regimens may require considerable expertise while, in most of the world, treatment by experts is unavailable. It would be an unfortunate and unintended consequence if physicians reverted to the use of weak TCSs to treat VLS, leading to undertreatment of many women. One controversial recommendation is the use of twicedaily application of corticosteroids for more severely affected patients with VLS. Evidence from findings after application to nongenital skin is that once-daily application of a corticosteroid is sufficient and that no further benefit may be derived from using it twice daily.12 Furthermore, increased absorption would be expected in the mucous membranes. We do not know whether a once- or twice-daily regimen is best in the vulva. Given that corticosteroid may be wiped off the genital site after urination, further study is needed. Even more problematic is the issue of managing VLS after the initial treatment period. Further treatment has been advocated in the past on an as-needed basis,10 guided by symptoms. Lee and colleagues1 argue that symptom control alone is not adequate and that treatment should be determined by the condition of the genital skin. Renaud-Vilmer and colleagues13 reported that 85% of their patients had a relapse of symptoms after the initial treatment ended, so it seems logical to proactively suppress the inflammatory component. We and many other vulvologists now recommend continuous maintenance therapy for VLS, even when asymptomatic. Virgili et al14 reported that twice-weekly application of mometasone furoate, 0.1%, ointment is an effective and safe way to prolong remission. Extrapolated evidence for this approach comes from atopic eczema, for which maintenance treatment is now the norm; patients are advised to get and ARTICLE INFORMATION Author Affiliations: Department of Dermatology, Oxford University Hospitals Trust, Oxford, England (Cooper); Department of Dermatology, P. D. Hinduja National Hospital and Medical Research Center, Mumbai, India (Madnani); Department of Dermatology, Sir HN Reliance Foundation Hospital, Mumbai, India (Madnani); Department of Obstetrics and Gynecology, Geisel School of Medicine, Dartmouth College, Hanover, New Hampshire (Margesson); Department of Surgery (Dermatology), Geisel School of Medicine, Dartmouth College, Hanover, New Hampshire (Margesson). Corresponding Author: Susan M. Cooper, MD, FRCP, Department of Dermatology, Oxford University Hospitals Trust, Oxford OX3 7LJ, England ([email protected]). Published Online: June 12, 2015. doi:10.1001/jamadermatol.2015.0644. Conflict of Interest Disclosures: None reported. REFERENCES 1. Lee A, Bradford J, Fischer G. Long-term management of adult vulvar lichen sclerosus: a prospective cohort study of 507 women [published online June 12, 2015]. JAMA Dermatol. doi:10.1001/jamadermatol.2015.0643. 2. Dalziel KL, Millard PR, Wojnarowska F. The treatment of vulval lichen sclerosus with a very
E2
keep control of their disease.15 A further benefit of maintenance treatment may be prevention of scarring, a distressing outcome of VLS. Lee et al1 present compelling evidence that scarring and progression of adhesions can be controlled by good adherence to treatment. In their compliant group, there was progression of scarring in only 12 (3.4%) vs 60 (40.0%) (P < .001) of those with partial or poor compliance. This study was conducted in the private sector where we presume that patients either had adequate health insurance or could afford to pay for their care. In many parts of the world, it is difficult to follow up patients as carefully and frequently as Lee et al did. In the United Kingdom, there is a national shortage of vulvar experts and dermatologists and there is a trend to take all perceived nonurgent cases back into the general practitioner community for care. In the United States and India, the fee-for-service model and the lack of knowledgeable practitioners present barriers to initial care and follow-up. In the United States, the recent increase in the cost of superpotent corticosteroids added another challenge. We congratulate the authors on an article that has profound implications for patients with VLS and their physicians worldwide. Until now, suppression of the disease has concerned physicians and has often been inadequate. The reduction in cancer among patients with VLS who were treated with TCSs is no longer speculative. This focus of concern can effectively communicate the message that long-term use of a TCS likely prevents the progression of VLS and the development of squamous cell carcinoma. Awareness, access, advice, affordability, and adherence all must align for appropriate care of VLS and prevention of vulvar cancer.
potent topical steroid (clobetasol propionate 0.05%) cream. Br J Dermatol. 1991;124(5):461-464.
adherence to topical therapy overestimate actual use. J Am Acad Dermatol. 2004;51(2):212-216.
3. Wallace HJ. Lichen sclerosus et atrophicus. Trans St Johns Hosp Dermatol Soci. 1971;57(1):9-30.
10. Neill SM, Lewis FM, Tatnall FM, Cox NH; British Association of Dermatologists. British Association of Dermatologists’ guidelines for the management of lichen sclerosus 2010. Br J Dermatol. 2010;163 (4):672-682.
4. Hart WR, Norris HJ, Helwig EB. Relation of lichen sclerosus et atrophicus of the vulva to development of carcinoma. Obstet Gynecol. 1975;45(4):369-377. 5. Carlson JA, Ambros R, Malfetano J, et al. Vulvar lichen sclerosus and squamous cell carcinoma: a cohort, case control, and investigational study with historical perspective; implications for chronic inflammation and sclerosis in the development of neoplasia. Hum Pathol. 1998;29(9):932-948. 6. Cooper SM, Gao XH, Powell JJ, Wojnarowska F. Does treatment of vulvar lichen sclerosus influence its prognosis? Arch Dermatol. 2004;140(6):702-706. 7. Urquhart J. The odds of the three nons when an aptly prescribed medicine isn’t working: non-compliance, non-absorption, non-response. Br J Clin Pharmacol. 2002;54(2):212-220. 8. Krejci-Manwaring J, McCarty MA, Camacho F, et al. Adherence with topical treatment is poor compared with adherence with oral agents: implications for effective clinical use of topical agents. J Am Acad Dermatol. 2006;54(5)(suppl): S235-S236. 9. Carroll CL, Feldman SR, Camacho FT, Manuel JC, Balkrishnan R. Adherence to topical therapy decreases during the course of an 8-week psoriasis clinical trial: commonly used methods of measuring
11. Jones RW, Scurry J, Neill S, MacLean AB. Guidelines for the follow up of women with vulvar lichen sclerosus in specialist clinics. Am J Obstet Gynecol. 2008;198(5):496e1-496e3. 12. Lagos BR, Maibach HI. Frequency of application of topical corticosteroids: an overview. Br J Dermatol. 1998;139(5):763-766. 13. Renaud-Vilmer C, Cavelier-Balloy B, Porcher R, Dubertret L. Vulvar lichen sclerosus: effect of long-term topical application of a potent steroid on the course of the disease. Arch Dermatol. 2004;140 (6):709-712. 14. Virgili A, Minghetti S, Borghi A, Corazza M. Proactive maintenance therapy with a topical corticosteroid for vulvar lichen sclerosus: preliminary results of a randomized study. Br J Dermatol. 2013;168(6):1316-1324. 15. Schmitt J, von Kobyletzki L, Svensson A, Apfelbacher C. Efficacy and tolerability of proactive treatment with topical corticosteroids and calcineurin inhibitors for atopic eczema: systematic review and meta-analysis of randomized controlled trials. Br J Dermatol. 2011;164(2):415-428.
JAMA Dermatology Published online June 12, 2015 (Reprinted)
Copyright 2015 American Medical Association. All rights reserved.
Downloaded From: http://archderm.jamanetwork.com/ by a Universite Laval User on 07/09/2015
jamadermatology.com
EDITORIAL
Reduced Risk of Squamous Cell Carcinoma With Adequate Treatment of Vulvar Lichen Sclerosus Susan M. Cooper, MD, FRCP; Nina Madnani, MD, DVD; Lynnette Margesson, MD, FRCPC
In this issue, Lee and colleagues1 present the results of the largest prospective clinical cohort study to date concerning 507 women with vulvar lichen sclerosus (VLS). The authors present evidence that poor compliance with topical corticosteroid (TCS) treatment predisposes patients to the development of Related article vulvar cancer and scarring. They propose that initial treatment regimens should be selected using a variety of corticosteroid potencies based on the severity of signs at presentation. They also propose that maintenance treatment for VLS should be the norm, increasing or decreasing the potency of treatment as necessary. The authors recommend life-long specialist follow-up. Development of vulvar skin cancer is a feared complication of VLS, but the exact risk of malignant transformation is uncertain. In studies described before the widespread introduction of superpotent corticosteroids for VLS treatment following the article by Dalziel et al in 1991,2 estimates of the development of squamous cell carcinoma were between 3% and 5%.3-5 In the poststeroid era, the second largest study from England, reported by one of us,6 estimated a risk of 2.4%; however, this risk increases to 4.0% if vulvar intraepithelial neoplasia (VIN) is included. The issue is complicated because previous studies3-5 did not include cases of VIN, and furthermore, the changes in classification of VIN mean that earlier studies may have included some cases of VIN with low potential for invasive squamous cell carcinoma. For years vulvologists have suspected that poor compliance with treatment might increase the risk of developing malignant neoplasms but have lacked proof because studies so far have lacked sufficient power to detect this difference. In the current study, Lee et al1 followed up 507 patients, tailoring their treatment to the clinical response, and assessed patients as being fully or partially compliant based on whether they self-reported that they followed instructions all or most of the time (fully compliant) or some, little, or none of the time (partially compliant). There was a statistically significant association between the risk of developing vulvar malignant neoplasms in the compliant group (357 [0%] women) vs the partially compliant group (150 [4.7%] women) (P < .001). Malignant neoplasms included 4 differentiated VIN and 3 invasive squamous cell carcinomas; however, differentiated VIN has a high potential to have invasive cells develop and therefore it is appropriate to include these cases. This article is an important contribution to our knowledge, providing the first evidence in women of the association between malignant neoplasms and poor compliance with treatment. This information will allow us to better inform our patients and encourage those who find it difficult to comply for various reasons.
The authors used self-reported compliance, with planned treatment as their only measure of compliance with TCS treatment. Compliance with oral medications is usually overestimated, with only one-sixth of patients who believe themselves to be compliant actually being fully compliant.7 Compliance with topical medications tends to be even lower than with oral treatments8 and decreases over time.9 Problems with using only 1 patient-reported measure include patients reporting what their physicians want to hear, forgetting missed treatments, and being overly optimistic about their compliance. In addition, compliance may vary during several years of treatment, decreasing when women forget about their asymptomatic disease or when important life events take over. Different health beliefs in some cultures can still be a barrier to compliance. Fear about perceived dangers of TCSs is still common and is not helped by package inserts that exhort patients to use TCSs for a short duration only and not to apply to mucous membranes. Furthermore, advice from dispensing pharmacists to use a product sparingly may contribute to anxieties. Elderly patients often have difficulty reaching the involved area. There are other ways of assessing compliance, such as recording the amount of corticosteroid used (by monitoring weight of tubes and prescriptions issued) or using diary charts and electronic capping of prescription containers. These measures may be appropriate for future studies. In this article, the reasons for poor compliance are not addressed but present a potentially fruitful area for future study. In the study by Lee et al,1 cohort treatment was tailored to the severity of disease, using the presence or absence and degree of hyperkeratosis as the principal marker of severity. The most severe cases with extensive hyperkeratosis were treated twice daily with a superpotent TCS and less severe cases with a reducedpotency TCS for the initial treatment period. This use is in contrast to the recommendations of guidelines.10,11 Starting with a superpotent corticosteroid has been advocated for all patients either as an initial 3-month once-daily regimen or a tapered regimen for 3 months. Signs at presentation vary considerably, with some women displaying severe widespread genital pallor, hyperkeratosis, fissures, and erosions whereas others show subtle pallor; there are yet others who are asymptomatic. Hyperkeratosis alone may not be a sufficient marker of active disease because ecchymoses and erosions may also be important. Tailoring treatment to the severity of the disease makes sense because in other inflammatory diseases, such as atopic eczema, dermatologists routinely tailor the potency of the corticosteroid used to the severity of the disease. Some patients in the study by Lee et al1 required more than 5 months of continuous treatment to control their symptoms. Could using a lesser potency of corticosteroid
jamadermatology.com
(Reprinted) JAMA Dermatology Published online June 12, 2015
Copyright 2015 American Medical Association. All rights reserved.
Downloaded From: http://archderm.jamanetwork.com/ by a Universite Laval User on 07/09/2015
E1
Opinion Editorial
lengthen the time it takes for the condition of the genital skin to improve? Introducing severity assessments and using varied regimens may require considerable expertise while, in most of the world, treatment by experts is unavailable. It would be an unfortunate and unintended consequence if physicians reverted to the use of weak TCSs to treat VLS, leading to undertreatment of many women. One controversial recommendation is the use of twicedaily application of corticosteroids for more severely affected patients with VLS. Evidence from findings after application to nongenital skin is that once-daily application of a corticosteroid is sufficient and that no further benefit may be derived from using it twice daily.12 Furthermore, increased absorption would be expected in the mucous membranes. We do not know whether a once- or twice-daily regimen is best in the vulva. Given that corticosteroid may be wiped off the genital site after urination, further study is needed. Even more problematic is the issue of managing VLS after the initial treatment period. Further treatment has been advocated in the past on an as-needed basis,10 guided by symptoms. Lee and colleagues1 argue that symptom control alone is not adequate and that treatment should be determined by the condition of the genital skin. Renaud-Vilmer and colleagues13 reported that 85% of their patients had a relapse of symptoms after the initial treatment ended, so it seems logical to proactively suppress the inflammatory component. We and many other vulvologists now recommend continuous maintenance therapy for VLS, even when asymptomatic. Virgili et al14 reported that twice-weekly application of mometasone furoate, 0.1%, ointment is an effective and safe way to prolong remission. Extrapolated evidence for this approach comes from atopic eczema, for which maintenance treatment is now the norm; patients are advised to get and ARTICLE INFORMATION Author Affiliations: Department of Dermatology, Oxford University Hospitals Trust, Oxford, England (Cooper); Department of Dermatology, P. D. Hinduja National Hospital and Medical Research Center, Mumbai, India (Madnani); Department of Dermatology, Sir HN Reliance Foundation Hospital, Mumbai, India (Madnani); Department of Obstetrics and Gynecology, Geisel School of Medicine, Dartmouth College, Hanover, New Hampshire (Margesson); Department of Surgery (Dermatology), Geisel School of Medicine, Dartmouth College, Hanover, New Hampshire (Margesson). Corresponding Author: Susan M. Cooper, MD, FRCP, Department of Dermatology, Oxford University Hospitals Trust, Oxford OX3 7LJ, England ([email protected]). Published Online: June 12, 2015. doi:10.1001/jamadermatol.2015.0644. Conflict of Interest Disclosures: None reported. REFERENCES 1. Lee A, Bradford J, Fischer G. Long-term management of adult vulvar lichen sclerosus: a prospective cohort study of 507 women [published online June 12, 2015]. JAMA Dermatol. doi:10.1001/jamadermatol.2015.0643. 2. Dalziel KL, Millard PR, Wojnarowska F. The treatment of vulval lichen sclerosus with a very
E2
keep control of their disease.15 A further benefit of maintenance treatment may be prevention of scarring, a distressing outcome of VLS. Lee et al1 present compelling evidence that scarring and progression of adhesions can be controlled by good adherence to treatment. In their compliant group, there was progression of scarring in only 12 (3.4%) vs 60 (40.0%) (P < .001) of those with partial or poor compliance. This study was conducted in the private sector where we presume that patients either had adequate health insurance or could afford to pay for their care. In many parts of the world, it is difficult to follow up patients as carefully and frequently as Lee et al did. In the United Kingdom, there is a national shortage of vulvar experts and dermatologists and there is a trend to take all perceived nonurgent cases back into the general practitioner community for care. In the United States and India, the fee-for-service model and the lack of knowledgeable practitioners present barriers to initial care and follow-up. In the United States, the recent increase in the cost of superpotent corticosteroids added another challenge. We congratulate the authors on an article that has profound implications for patients with VLS and their physicians worldwide. Until now, suppression of the disease has concerned physicians and has often been inadequate. The reduction in cancer among patients with VLS who were treated with TCSs is no longer speculative. This focus of concern can effectively communicate the message that long-term use of a TCS likely prevents the progression of VLS and the development of squamous cell carcinoma. Awareness, access, advice, affordability, and adherence all must align for appropriate care of VLS and prevention of vulvar cancer.
potent topical steroid (clobetasol propionate 0.05%) cream. Br J Dermatol. 1991;124(5):461-464.
adherence to topical therapy overestimate actual use. J Am Acad Dermatol. 2004;51(2):212-216.
3. Wallace HJ. Lichen sclerosus et atrophicus. Trans St Johns Hosp Dermatol Soci. 1971;57(1):9-30.
10. Neill SM, Lewis FM, Tatnall FM, Cox NH; British Association of Dermatologists. British Association of Dermatologists’ guidelines for the management of lichen sclerosus 2010. Br J Dermatol. 2010;163 (4):672-682.
4. Hart WR, Norris HJ, Helwig EB. Relation of lichen sclerosus et atrophicus of the vulva to development of carcinoma. Obstet Gynecol. 1975;45(4):369-377. 5. Carlson JA, Ambros R, Malfetano J, et al. Vulvar lichen sclerosus and squamous cell carcinoma: a cohort, case control, and investigational study with historical perspective; implications for chronic inflammation and sclerosis in the development of neoplasia. Hum Pathol. 1998;29(9):932-948. 6. Cooper SM, Gao XH, Powell JJ, Wojnarowska F. Does treatment of vulvar lichen sclerosus influence its prognosis? Arch Dermatol. 2004;140(6):702-706. 7. Urquhart J. The odds of the three nons when an aptly prescribed medicine isn’t working: non-compliance, non-absorption, non-response. Br J Clin Pharmacol. 2002;54(2):212-220. 8. Krejci-Manwaring J, McCarty MA, Camacho F, et al. Adherence with topical treatment is poor compared with adherence with oral agents: implications for effective clinical use of topical agents. J Am Acad Dermatol. 2006;54(5)(suppl): S235-S236. 9. Carroll CL, Feldman SR, Camacho FT, Manuel JC, Balkrishnan R. Adherence to topical therapy decreases during the course of an 8-week psoriasis clinical trial: commonly used methods of measuring
11. Jones RW, Scurry J, Neill S, MacLean AB. Guidelines for the follow up of women with vulvar lichen sclerosus in specialist clinics. Am J Obstet Gynecol. 2008;198(5):496e1-496e3. 12. Lagos BR, Maibach HI. Frequency of application of topical corticosteroids: an overview. Br J Dermatol. 1998;139(5):763-766. 13. Renaud-Vilmer C, Cavelier-Balloy B, Porcher R, Dubertret L. Vulvar lichen sclerosus: effect of long-term topical application of a potent steroid on the course of the disease. Arch Dermatol. 2004;140 (6):709-712. 14. Virgili A, Minghetti S, Borghi A, Corazza M. Proactive maintenance therapy with a topical corticosteroid for vulvar lichen sclerosus: preliminary results of a randomized study. Br J Dermatol. 2013;168(6):1316-1324. 15. Schmitt J, von Kobyletzki L, Svensson A, Apfelbacher C. Efficacy and tolerability of proactive treatment with topical corticosteroids and calcineurin inhibitors for atopic eczema: systematic review and meta-analysis of randomized controlled trials. Br J Dermatol. 2011;164(2):415-428.
JAMA Dermatology Published online June 12, 2015 (Reprinted)
Copyright 2015 American Medical Association. All rights reserved.
Downloaded From: http://archderm.jamanetwork.com/ by a Universite Laval User on 07/09/2015
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![[Vulvar Squamous cell carcinoma: Why monitor a lichen sclerosus].](/assets/img/hold.png)
