Are You Confident of the Diagnosis?
What you should be alert for in the history
Changes associated with actinic cheilitis develop slowly over time. It is a result of chronic sun exposure. People often complain of severely dry, flaking lips. It is associated with a rough texture, loss of lip volume with rhytid formation, white or red color change, and possible burning sensation. Patients report involvement of localized or diffuse areas involving the lower and/or upper lip.
Characteristic features on physical examination
On physical examination, the following signs can be appreciated: scaly erythematous patches (localized or diffuse), atrophy, swelling or edema, white or gray color change, areas of pallor, ulcerations or erosions, rough texture, blunting of the separation between the mucosal and cutaneous lip, loss of the white roll, and increased vertical fissuring and rhytides (Figure 1, Figure 2). These changes are more commonly seen on the lower lip vermillion border.
Expected results of diagnostic studies
A biopsy is the diagnostic study of choice. The histopathologic features associated with actinic cheilitis are: solar elastosis, hyperkeratosis, hypergranulosis, acanthosis or epidermal atrophy, and epithelial dysplasia. Epithelial dysplasia is based on the degree of the following: hyperplasia of the basal cell layer, epithelial maturation, crowding, mitotic activity, pleiomorphism, and hyperchromatic nuclei. The degree of dysplasia can range from mild to severe. The severe end of the spectrum should be closely evaluated to assess for possible advancement to invasive squamous cell carcinoma.
The changes found on histology allow other clinically similar entities to be ruled out. Acute erythema and scaling can be secondary to an allergic contact or irritant contact dermatitis. These entities are more acute, are associated with pruritus and/or burning, and are steroid responsive. Habitual lip licking will also result in scaly erythematous patches, but this more commonly happens in younger patients, involves the upper and lower lip, and does not flatten the vermillion border.
Improvement and resolution of these changes will occur by keeping the area free of irritating substances and utilizing a low potency topical steroid. Resolution of symptoms of actinic cheilitis will not occur with this treatment regimen.
Cheilitis glandularis is an inflammatory condition that causes eversion of the lower lip and can blunt the separation of the mucosal and cutaneous lip. There are dilated ductal openings found on the mucosa that can express viscous fluid. Although cheilitis glandularis is a separate entity and should not show any atypia on histology, oftentimes there is overlap between the two presentations. It is likely that the eversion of the lower lip seen in cheilitis glandularis allows for increased UV exposure and increases the potential for developing actinic cheilitis.
Who is at Risk for Developing this Disease?
Fair-skinned individuals with skin type I and II are most at risk for developing actinic cheilitis. It is most common in Caucasian males over the age of 40. Those who work outdoors or spend significant time outside are at an increased risk. Women have been thought to be at less risk because they are more likely to wear a protective barrier (ie, lipstick or sun block).
What is the Cause of the Disease?
Chronic ultraviolet (UV) exposure leads to dysplastic changes of the epidermis. UV exposure causes damage to DNA in the epithelial cells of the lip. It has also been found that exposure to UV light can inhibit antigen presenting cells and weaken the surveillance efforts of the immune system to detect cellular damage and DNA mutation. Previous studies have shown an increase in p53 expression and a decrease in bcl-2 in patients with actinic cheilitis when compared to non-damaged lip epithelium.
Systemic Implications and Complications
Untreated actinic cheilitis leads to two times the risk of developing a squamous cell carcinoma (SCC) of the lip. There is a significantly higher incidence of metastasis of invasive squamous cells of the lip when compared to a nonmucosal location, 11% versus 1%.
All patients with transformation to invasive SCC on the lip should have a lymph node evaluation. If the invasive SCC is greater than 2 cm, shows a thickness of 2 mm or more, or is poorly differentiated with perineural involvement on pathology, then a computed tomography (CT) scan of the head and neck should be considered to evaluate for metastasis.
If imaging and/or physical examination show lymphadenopathy, then a lymph node biopsy and dissection would be appropriate. In very aggressive, poorly differentiated tumors on the lip, a sentinel lymph node biopsy might be considered.
Topical treatments (ie, chemotherapeutic versus immunotherapy)
Trichloroacetic Acid Peel 50%
Localized shave removal
CO2 laser resurfacing
Er:YAG laser resurfacing
Photodynamic therapy (PDT)
Optimal Therapeutic Approach for this Disease
Cryosurgery is a simple procedure that can be performed to effectively treat localized actinic damage. Cryosurgery works at both the cellular and vascular level to induce necrosis of the epidermis. To be effective, it commonly requires multiple freeze-thaw cycles of liquid nitrogen to the dysplastic areas. It is a good option for localized areas of actinic damage and can be performed by most physicians. Attachments can be used to avoid unnecessary treatment of uninvolved mucosa and/or skin. It is a quick and inexpensive procedure. No local anesthetic is required.
The potential side effects that result are: swelling, blistering, ulceration, pain both during and after the procedure, hypo/hyperpigmentation, scarring, and potential induction of herpes labialis. One clinical study reported a 96% cure rate after treatment of actinic cheilitis with cryosurgery.
Electrosurgery and localized shave removal are also effective options for discrete areas of actinic cheilitis. Both procedures involve destruction or removal of clinically involved areas of actinic damage. Local anesthetic is required. Shave removal provides histologic evaluation to confirm that the dysplastic area has been completely removed. Electrosurgery uses electrical current to cause destruction of the localized area of actinic damage.
Potential side effects experienced with both procedures are: edema, pain, dyschromia, scarring, prolonged healing time, and potential activation of herpes labialis. No serious side effects are associated with these modalities and both are relatively simple and inexpensive. One study showed similar clinical results when comparing electrodessication with CO2 ablation, but electrodessication was shown to have an increased healing time for complete reepithelialization.
Carbon dioxide (CO2) laser ablation is one of the most effective treatments for extensive actinic cheilitis. The CO2 laser emits infrared light at 10,600-nm wavelength that targets water resulting in the disruption of the cell membrane and cell death. The epidermis is ablated with the laser treatment, resulting in effective clearance of all dysplastic epithelial changes. Coagulation occurs with every pass of the laser and a moist gauze can be used to remove the char in order to evaluate the depth of treatment.
Previous studies have reported that the superpulsed mode has less potential side effects than the continuous wave form. The superpulsed mode reduces the potential for collateral damage by concentrating the energy into rapid pulses with adequate cooling between pulses. The ultrapulsed mode has also shown to be an effective way of delivering powerful, rapid pulses for successful treatment with minimal collateral damage. Expected wound healing time and potential for scarring are decreased with these methods.
The exact settings and handpieces will depend on the CO2 laser being used, but one will generally aim for a setting of 18W and one to two passes, depending on the extent of involvement. We use the Sharpon Silktouch CO2 laser mode with a setting of 18W. One study reported using the Paragon 50 short-pulsed CO2 laser with the Parascan Handpiece for one pass with settings of 18W (360mJ/cm2), 20% overlap in a 7×3.5-mm rectangular pattern.
Multiple studies have shown that the CO2 is extremely effective at treating actinic cheilitis and posttreatment biopsies have confirmed complete clearance. The procedure is performed under local anesthetic and nerve blocks. The ablation of the epithelium can result in 1-2 weeks of downtime with need for frequent soaks and application of petroleum based emollients.
The potential risk for infection and activation of herpes labialis is greater than with previously mentioned treatment methods. It may be prudent to place those treated on a prophylactic antibiotic and antiviral treatment (ie, valcyclovir or acyclovir). Other potential side effects include: edema, pain during and after the procedure, dyschromia, scarring, paresthesias, and delayed wound healing.
When compared to surgical vermilionectomy, CO2 laser ablation results are less operator dependent, do not result in lip contour irregularities or changes, involve less downtime, are less likely to cause difficulty eating, and will not result in postoperative complications like dehiscence and hematoma formation. CO2 ablation for actinic cheilitis can be performed in conjunction with Mohs surgery when there is an invasive squamous cell carcinoma with surrounding actinic damage.
Erbium:yttrium-aluminum-garnet (Er:YAG) laser ablation has recently been discussed as a potential treatment for actinic cheilitis. The Er:YAG laser emits infrared light at 2940-nm wavelength that targets water and also leads to destruction of the cell membrane and ablation of the epidermis. Although there is little in the literature at this time, the mechanism of action is similar to the CO2 ablation and therefore appears to be a good treatment option.
The following settings were reported in a recent case series report. A combination of an ablative (1J/cm2, with a variable pulse width up to 400 microseconds) pass and a coagulation (<1J/cm2, with a pulse width between 2-35 ms) pass were used. The treatment consisted of: a 4-mm spot 100 micrometer ablation and two 4-mm spot combined 100 micrometer ablation and 100 micrometer coagulation passes. Additional passes (up to four) were performed in focal areas that showed clinical persistence. The final endpoint was visualization of normal dermal surface.
This series showed high cure rates of up to 84.8% with low morbidity and excellent cosmetic results. Aftercare and potential side effects are similar to those discussed above with CO2 ablation.
Vermilionectomy is by far the most successful treatment for actinic cheilitis because it not only surgically removes the dysplastic area but also allows for histologic confirmation of clear margins and no invasive component. One study in the literature found no clinical or histologic recurrences at 4 years for those cases of actinic cheilitis treated with vermilionectomy. Despite its high cure rates, this procedure is often not first line because it is operator dependent and an increased risk of morbidity is associated with the procedure.
Surgical vermilionectomy is often reserved for severe actinic cheilitis or done intraoperatively in cases where an invasive squamous cell carcinoma has been removed and surrounding actinic damage is noted. Vermilionectomy involves surgically resecting the full thickness atypical epithelium either down to the orbicularis oris muscle (simple vermilionectomy) or includes removal of muscle and glans (modified vermilionectomy). After the removal of the dysplastic epithelium, a labial mucosa advancement flap is performed.
Potential postoperative complications associated with this procedure are: hematoma, dehiscence, functional impairment, asymmetry and contour distortion, scarring, and paresthesias.
Topical treatments with chemotherapy and immunotherapy (topical 5-fluourouracil and imiquimod) have been successful at treating actinic cheilitis as they offer a nonsurgical option for field treatment. Both are potentially effective treatments, but they are limited by the low rate of patient compliance.
5-fluourouracil (5-FU) is an antimetabolite that inhibits thymidylate synthetase, an enzyme necessary for the production of DNA and RNA. Neoplastic cells are known to have an increased rate of mitosis and are therefore preferentially targeted. The disruption of metabolic activity leads to cell death and destruction of dysplastic cells. There are different regimens suggested but the most effective for 5-FU has been shown to be twice daily application to the area for 2-4 weeks. Length of treatment varies based on the clinical response.
Patients will experience an inflammatory reaction with edema, oozing, and likely ulceration or erosion formation. These symptoms can occur throughout the treatment course and can be decreased with topical steroid application. Reactions can be severe and intolerable for patients because of duration of treatment and impact on ability to eat, drink, and speak.
There is a high rate of patient noncompliance seen because of these side effects. Treatment can be associated with pain and sun sensitivity, and it may be prudent to do antiviral prophylaxis if patients have a history of herpes labialis. Previous studies have shown that histologic dysplasia is likely to recur within a few years of treatment.
Imiquimod cream is an immune stimulator that is believed to cause an upregulation of proinflammatory cytokines, through Toll-like receptor 7, resulting in cellular apoptosis of dysplastic cells. It has also been effectively used to treat subclinical actinic damage. There are many different treatment regimens performed with 5% imiquimod, varying from 3-5 times a week for 3-16 weeks. A small study showing successful histologic clearance, applied imiquimod 3 times a week for 4-6 weeks and showed no evidence of clinical recurrence in 3 months.
Imiquimod 3.75% cream is a relatively new formulation that has shown similar efficacy as the imiquimod 5% cream for the treatment of actinic keratoses. This 3.75% cream has a shorter treatment course and is able to treat a larger surface area. The recommended treatment regimen is daily application of the cream for 2 weeks, a 2-week nontreatment period, and then an additional 2-week treatment cycle.
The potential side effects for imiquimod treatment are similar to treatment with 5-FU. Patients can expect erythema, edema, discomfort, oozing, and potential ulceration or erosion formation. Compliance is an issue with this medication because of these side effects and the impact on daily activities (ie, eating, drinking, talking). As with 5-FU treatment, there is usually good cosmetic outcome with minimal risk of scarring. Antiviral prophylaxis should be considered in those with a history of herpes labialis. A potential link between imiquimod treatment and aphthous ulcer formation has been reported.
PDT is becoming a more commonly used procedure to treat actinic damage. The literature shows anywhere from 50-90% response rate with this treatment. It involves applying a photosensitizing agent, ie, 5-aminolevulinic acid ( 5-ALA) or methyl-ester 5-aminolevulinic acid (MAL), to the affected area and activating it with a specific light source. Proliferating cells preferentially take up the photosensitizing agent. The light source converts it to Protoporphyrin IX, leading to radical oxygen species formation and cell death. These changes occur in more actively dividing cells, therefore targeting the dysplastic cellular areas.
In order to perform the treatment, the area must first be lightly curetted to remove the scale and allow for better penetration of the photosensitizing agent. After hemostasis is achieved, the 5-ALA or MAL is then applied and occluded for 2-4 hours. The area is then exposed to either a blue light source (417nm) for activation of the 5-ALA or a red light source (650nm) for the activation of the MAL.
For PDT using 5-ALA, the exposure to blue light is for 16 minutes and 40 seconds, with a total light source of 10J/cm2. For MAL treatment, the exposure to red light for 8 minutes and 40 seconds with a total light source of 37J/cm2 has been successfully used. A total of 2-5 sessions every 2-4 weeks is recommended.
Potential side effects include: localized pain and burning during and after the treatment, edema, blistering, crusting, photosensitivity, and reactivation of herpes labialis. Overall, the side effects are generally milder and more tolerable than some of the other treatments. Good cosmetic results and functionality have been reported.
Dermabrasion is a procedure that uses a diamond fraise tip to mechanically remove the surface of the epithelium. It has recently been reported to be an effective treatment for actinic cheilitis. It can be used intraoperatively after removal of an invasive SCC of the lip to treat the surrounding actinic damage. One to two passes with a fine pear-shaped diamond fraise tip is used to remove the epithelium. The endpoint is visualization of the dermis with a dull appearance and pinpoint bleeding.
The device should rotate toward the orifice to avoid any irregularities and feathering should be performed along the cutaneous border to avoid lip margin scarring. Re-epithelialization takes about 1-2 weeks. Topical wound care with emollients (ie, petrolatum) should be performed until re-epithelialization is complete.
Potential side effects include: minimal discomfort, swelling and edema, crusting, and potential herpes labialis reactivation. Benefits include less downtime and potential for scarring than when compared to CO2 ablation, good cosmetic outcome, and quick and easy low-cost treatment that is less operator dependent.
Trichloroacetic Acid (TCA) 50% chemical peels nonselectively destroy both the epithelium and superficial dermis. Although the literature is limited, it has not shown this method to be very successful. One small study showed initial clinical improvement of all patients, but at 1 year, 70% had clinical recurrence and 100% had histologic recurrence of dysplasia. Reepithelialization can take 1-3 weeks. Potential side effects include: mild discomfort, crusting, edema, and herpes labialis reactivation.
Patients should be monitored to ensure complete reepithelialization of the mucosa post treatment. I would recommend initially reevaluating at 3 months posttreatment to ensure effective treatment and persistent clearance. If topical therapy is chosen, it is important to monitor for compliance.
Follow-up is dependent on patient history, degree of actinic cheilitis, and association of an invasive SCC. Those with a history of moderate/severe actinic cheilitis and associated invasive SCC should be followed more closely for signs of recurrence or metastasis. For the first year, clinical examination with lymph node evaluation every 3 months is recommended. Photoprotection must be strongly recommended and avoidance of other potentially contributing factors (ie, smoking, tobacco chewing) should be encouraged.
If actinic damage does not improve or recurs within 1 year post treatment, then a new treatment modality should be used. If lesions continue to recur or are ulcerated, biopsy to rule out invasive component is recommended prior to continued treatment. When an SCC of the lip is present with surrounding actinic cheilitis, Mohs surgery for SCC removal should be performed in conjunction with either surgical or ablative laser vermilionectomy.
It is important to remind patients and their families that there is a high risk of metastasis (11%) for an SCC of the lip, so in moderate/severe cases of actinic cheilitis more invasive procedures, like vermilionectomy and CO2 ablation, are worth the risk. Topical chemotherapeutic and immunomodulatory therapies are not always appropriate.
Unusual Clinical Scenarios to Consider in Patient Management
It is important to remember that any condition that causes chronic lip enlargement and eversion, such as seen in the Melkersson-Rosenthal syndrome or with cheilitis glandularis, may have a higher incidence of actinic cheilitis.
What is the Evidence?
Shah, AY, Doherty, SD, Rosen, T. “Actinic cheilitis: a treatment review”. Int J Dermatol. vol. 49. 2010. pp. 1225-34. (This article is a thorough review of all of the treatment options that have been used to treat actinic cheilitis. It reviews the literature for each treatment modality and grades the evidence-based strength of each therapeutic option. The review article effectively shows the evidence for each type of treatment and how these treatments compare to one another in controlled studies.)
Picascia, DD, Robinson, JK. “Actinic cheilitis:a review of the etiology, differential diagnosis, and treatment”. J Am Acad Dermatol. vol. 17. 1987. pp. 255-64. (Picascia and Robinson give a comprehensive review of the etiology, clinical spectrum, histology, and treatment options for actinic cheilitis. This review discusses in depth the differential diagnosis for actinic cheilitis and the signs used to differentiate these entities.)
Cavalcante, ASR, Anbinder, AL, Carvalho, YR. “Actinic cheilitis: clinical and histological features”. J Oral Maxillofac Surg. vol. 66. 2008. pp. 498-503. (The article presents the results of a small study performed to evaluate the clinical and histologic changes seen with actinic cheilitis. Specific trends are noted among subjects and these results are helpful guidelines to use for diagnosis. This article is a good reference for histologic changes seen in actinic cheilitis.)
Sachs, DL, Kang, S, Hammerberg, C, Helfrich, Y, Karimipour, D, Orringer, J. “Topical fluorouracil for actinic keratoses and photoaging: A clinical and molecular analysis”. Arch Dermatol. vol. 145. 2009. pp. 659-66. (The nonrandomized, open-label prospective study evaluated the clinical and molecular changes seen after treatment of actinic damage with 5-fluorouracil 5% cream for 2 weeks. The study showed clinical improvement after the treatment course and molecular analysis confirmed production of pro-inflammatory mediators and keratin 16 production during and after treatment. There were increased levels of procollagen types I and III that would support the role of wound healing and dermal remodeling that follows the inflammatory phase of treatment. These findings reported in the study help to illustrate the mechanism of action for 5-fluorouracil treatment.)
Laws, RA, Wilde, JL, Grabski, WJ. “Comparison of electrodessication with CO2 laser for the treatment of actinic cheilitis”. Dermatol Surg. vol. 26. 2000. pp. 349-53. (The authors report a small prospective study that compares the treatment of actinic cheilitis with electrodessication versus CO2 ablation. The study was well designed, with a split lower lip being treated with one side receiving electrodessication and the other CO2 ablation. Although the sample size was too small for significant comparison of histologic results, the clinical results showed comparable results between the two treatment modalities. It was also shown that electrodessication was found to have a longer healing time then CO2 ablation.)
Armenores, P, James, CL, Walker, PC, Huilgol, SC. “Treatment of actinic cheilitis with the Er:YAG laser”. J Am Acad Dermatol. vol. 63. 2010. pp. 642-6. This article is a retrospective case series that presents the results of the use of an Er:YAG laser to treat actinic cheilitis. It provides support for use of this method, the treatment parameters used, and final outcome of treatment. Although the authors state that the Er:YAG is a good first-line treatment for actinic cheilitis with low recurrence rates, further studies with stronger evidence are need to support these promising results.)
Robinson, JK. “Actinic cheilitis. A prospective study comparing four treatment methods”. Arch Otolaryngol Head Neck Surg. vol. 115. 1989. pp. 848-52. (In this article, forty patients with actinic cheilitis were treated with one of four treatment modalities (topical 5-FU, TCA peel, shave removal, or CO2 ablation of the vermilion border) and the results were compared. This comparative study was an effective way of showing the different treatment options, success rates, and evidence behind favoring one versus the other. It confirmed that surgical removal (via shave) and CO2 ablation have the lowest recurrence rates and are the favored treatment options.)
Tsoukas, M. “Treatment of actinic keratosis with 5-ALA PDT versus topical imiquimod in healthy and immunosuppressed patients”. Melanoma Res. vol. 20. 2010. pp. e39-40. (This is an abstract that presents evidence for the use of PDT to treat actinic keratoses more effectively than imiquimod cream. It does a split face trial of the two treatment regimens on subjects with actinic damage that are immunocompetent and those that are immunosuppressed. It reports similar efficacy among immunocompetent patients, but PDT treatment proves to be more successful in immunosuppressed patients. This report is not only a good comparison for the two treatment regimens, but also a good reminder that treatment for immunosuppressed patients may be more difficult.)
Rossi, R, Assad, GB, Buggiani, G, Lotti, T. “Photodynamic therapy: treatment of choice for actinic cheilitis”. Dermatol Therapy. vol. 21. 2008. pp. 412-15. (The article reports the results of a case series of five patients with actinic cheilitis who were successfully treated with MAL PDT treatment with no evidence of recurrence at 30 months. This is a small study group but it does suggest that PDT is a reasonable treatment for actinic cheilitis with good cosmetic outcomes. This paper gives a detailed description of the treatment regimen used. Further studies are warranted with histologic evaluation to confirm that treatment of actinic cheilitis is successful with PDT.)
Dufresne, RG, Cruz, AP, Zeikus, P, Perlis, C, Jellinek, NJ. “Dermabrasion for actinic cheilitis”. Dermatol Surg. vol. 34. 2008. pp. 848-50. (The authors of this article present a small case series of four patients with actinic cheilitis that were successfully treated with intraoperative dermabrasion. The technique used is well described and the theory behind its success is adequately discussed. The evidence is not strong and further studies should be performed to confirm the effectiveness of dermabrasion for the treatment of actinic cheiltis.)
Cohen, JL. “Erbium laser resurfacing for actinic cheilitis”. J Drugs Dermatol. vol. 12. 2013. pp. 1290-2. (Actinic cheilitis is a precursor to squamous cell carcinoma which has a high rate of recurrence and metastasis. There are multiple treatment options. This article discusses the use of erbium laser resurfacing in cases where there is clinical or histologic findings consistent with actinic cheilitis and for resurfacing of the remaining lip surface after excisional removal of a squamous cell carcinoma.)
Jadotte, YT, Schwartz, RA. “Solar cheilosis:an ominous precursor part I. Diagnostic insights”. J Am Acad Dermatol. vol. 66. 2012. pp. 173-84. (Solar cheilosis, also known as actinic cheilitis, is a precursor to squamous cell carcinoma of the lip. Solar cheilosis is a precancerous change that is linked to ultraviolet light induced atypia. There are numerous factors involved in its development. This article does a thorough review of 142 peer reviewed articles.)
Jadotte, YT, Schwartz, RA. “Solar cheilosis:an ominous precursor part II. Therapeutic perspectives”. J Am Acad Dermatol. vol. 66. 2012. pp. 187-98. (This is a review article evaluating available reported treatment options for solar cheilosis. It reviews literature focused on topical, ablative, and surgical treatments and their rates of success.)
Zaiac, M, Clement, A. “Treatment of actinic cheilitis by photodynamic therapy with 5- aminolevulinic acid and blue light activation”. J Drugs Dermatol. vol. 10. 2011. pp. 1240-5. (This study evaluated the treatment of actinic cheilitis in 15 patients. The patients were treated with two 5-aminolevulinic acid PDT treatments with blue light activation. Results showed 65-75% clearance at 3-5 weeks after the first treatment and greater than 75% clearance 1 month after the second treatment.)
Sotiriou, E, Lallas, A, Goussi, C. “Sequential use of photodynamic therapy and imiquimod 5%cream for the treatment of actinic cheilitis:a 12 month follow-up study”. Br J Dermatol. vol. 165. 2011. pp. 888-92. (A study was performed on 34 patients with actinic cheilitis. The patients were treated with two sessions of methyl-aminolaevulinate-PDT followed by a 4 week course of imiquimod 5% cream three times a week. They found complete clinical cure rate at 12 months to be 80% and histologic complete cure rate to be 73%.)
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- Are You Confident of the Diagnosis?
- Who is at Risk for Developing this Disease?
- What is the Cause of the Disease?
- Systemic Implications and Complications
- Treatment Options
- Optimal Therapeutic Approach for this Disease
- Patient Management
- Unusual Clinical Scenarios to Consider in Patient Management
- What is the Evidence?