Category Archive Dermatology (A-Z)

What is Shingles? – Causes, Symptoms, Treatment

Shingles are the reactivation of a viral infection in the nerves to the skin that causes pain, burning, or a tingling sensation, along with an itch and blisters in the skin supplied by the affected nerve.  It is caused by the varicella-zoster virus, or VZV—the same virus that causes chickenpox.  When the itchy red spots of childhood chickenpox disappear, the virus remains in a dormant state in our nerve cells, ready to strike again in later life.  This second eruption of the chickenpox virus is called shingles or herpes zoster.

You cannot develop shingles unless you have had earlier exposure to chickenpox.  Shingles occur when an unknown trigger causes the virus to become activated.  Most adults who have the dormant virus in their bodies never get shingles.

What are the symptoms and signs of shingles?

The first symptom of shingles is often burning or tingling pain, or itch, generally in a band-like distribution on one side of the body, i.e.,  around the waist, chest, stomach, or back.   Shingles’ pain can be mild or intense.  Some people have mostly itching; some feel severe pain from the gentlest touch, such as the weight of bed linens or clothing.  A few people may have general symptoms of a viral infection, like fatigue, fever, and headache.

After several days or up to two weeks after the first symptoms are felt, a rash of fluid-filled blisters (vesicles) appears. These are similar to chickenpox but occur in a cluster rather than scattered over the body. The number of vesicles is variable.  Some rashes merge and produce an area that looks like a burn. Other people may have just a few small scattered lesions.  The clusters most often appear in a band called a dermatome, which contains nerves that branch out from the virus-affected nerve root exiting the spine.  The second most common location is on one side of the face around the eye and on the forehead.  However, shingles can involve any part of the body, including internal organs.

Recent studies have shown that subtle cases of shingles with only a few blisters, or none, are more common than previously thought. These cases may remain unrecognized.

Before the rash breaks out you usually feel tired and run-down. You may also have a slight fever and tingling sensations under your skin. The typical symptoms of shingles start 2 or 3 days later:

  • moderate to severe stinging or burning pain in the affected area,
  • followed by slightly reddish patches of skin with small bumps,
  • which then turn into small blisters that may be itchy in just a few hours.

This stage can last up to five days. After that, the blisters dry up in 2 to 10 days, leaving behind yellowish scabs.

The shingle rash generally affects only one side of the body and typically forms a band across the skin.

What is the varicella-zoster virus and how does it cause shingles?

The word “varicella” is derived from “variola,” the Latin word for smallpox. “Zoster” is the Greek word for girdle; shingles often produce a girdle or belt of blisters or lesions around one side of the waist.  This striking pattern also underlies the condition’s common name:  shingles come from “cingulum,” the Latin word for belt or girdle.

VZV belongs to a group of viruses called herpes viruses.  This group includes the herpes simplex virus (HSV) that causes cold sores, fever blisters, and genital herpes. Like VZV, HSV can hide in the nervous system after initial infection and then travel down nerve cell fibers to cause a renewed infection.  Repeated episodes of cold sores on the lips are the most common example.

Most adults in the United States have had chickenpox, even if it was so mild as to pass unnoticed, and they are at risk for developing shingles later in life.  In the original exposure to VZV (chickenpox), some of the virus particles settle into nerve cells (neurons) of sensory ganglia (a group of nerve cells that connect the sensory periphery and central nervous system), where they remain for many years in an inactive, hidden (latent) form.  The neurons in the sensory ganglia have nerve fibers that supply the skin and relay information to the brain about what the body is sensing—heat, cold, touch, pain.

When the VZV reactivates, it spreads down the long nerve fibers (axons) that extend from the sensory cell bodies to the skin. As the virus multiplies, the telltale rash erupts. With shingles, the nervous system is more deeply involved than it was during the bout with chickenpox, and the symptoms are often more complex and severe.

How are chickenpox and shingles different?

When a person, usually a child, who has not received the chickenpox vaccine is exposed to VZV, he or she usually develops chickenpox, a highly contagious disease that can be spread by breathing as well as by contact with the rash.  The infection begins in the upper respiratory tract where the virus incubates for 15 days or more. VZV then spreads to the bloodstream and migrates to the skin, giving rise to the familiar chickenpox rash.

In contrast, you can’t catch shingles from someone else.  You must already have been exposed to chickenpox and harbor the virus in your nervous system to develop shingles. When reactivated, the virus travels down nerves to the skin, causing the painful shingles rash.  In shingles, the virus does not normally spread to the bloodstream or lungs, so the virus is not shed in air.

But a person with a shingles rash—which contains active virus particles—can pass the virus to someone who has never had chickenpox or who has not been vaccinated.  In this case, the person will develop chickenpox, not shingles.  A person must come into direct contact with the open sores of the shingles rash.  Merely being in the same room with someone who has shingles will not cause chickenpox. Children who develop chickenpox generally fully recover; however, adults who develop chickenpox can become seriously ill.

Likewise, a person with chickenpox cannot give shingles to someone else—but they can pass the virus to someone who has never had chickenpox.

Who is at risk for shingles?

Anyone who had previously had chickenpox is at risk for shingles. About 25 percent of all adults, mostly otherwise healthy, will get shingles during their lifetime, usually after age 50.  The incidence increases with age so that shingles is 10 times more likely to occur in adults over 60 than in children under 10.  People with compromised immune systems, a natural consequence of aging or from the use of immunosuppressive medications such as prednisone, are at increased risk of developing shingles. Immune-suppressive drugs are used to treat serious illnesses such as cancer or from chemotherapy or radiation treatment, or from infection with HIV. Some individuals can also have re-eruptions and some, particularly those with significantly impaired immunity from drugs and diseases, may have shingles that spread over the body.

Youngsters whose mothers had chickenpox late in pregnancy—5 to 21 days before giving birth—or who had chickenpox in infancy have an increased risk of pediatric shingles.  Sometimes these children are born with chickenpox or develop a typical case within a few days

How are shingles treated?

Currently, there is no cure for shingles, but attacks can be made less severe and shorter by using prescription antiviral drugs such as acyclovir, valacyclovir, or famciclovir as soon as possible after symptoms begin.  Early treatment can reduce or prevent severe pain and help blisters dry faster. Antiviral drugs can reduce by about half the risk of being left with postherpetic neuralgia, which is chronic pain that can last for months or years after the shingles rash clears.  Doctors recommend starting antiviral drugs at the first sign of the shingles rash, or if the telltale symptoms indicate that a rash is about to erupt.  Other treatments to consider are anti-inflammatory corticosteroids such as prednisone.  These are routinely used when the eye or other facial nerves are affected.

Most people with shingles can be treated at home.

People with shingles should also try to relax and reduce stress (stress can make pain worse and lead to depression); eat regular, well-balanced meals; and perform gentle exercises, such as walking or stretching to keep active and stop thinking about the pain (but check first with your physician).  Placing a cool, damp washcloth on the blisters—but not when wearing a topical cream or patch—can help blisters dry faster and relieve pain.  Keeping the area clean can help avoid a secondary bacterial infection.

Can shingles be prevented?

Shingles vaccine

In May 2006, the Food and Drug Administration (FDA) approved a VZV vaccine (Zostavax) for use in people 60 and older who have had chickenpox.  In March 2011, the FDA extended the approval to include adults ages 50-59. A new shingles vaccine called Shingrix was licensed by the FDA in 2017 for adults age 50 and older. Talk with your healthcare professional if you have questions about shingles vaccination.

The Shingles Prevention Study—a collaboration between the Department of Veterans Affairs, the National Institute of Allergy and Infectious Diseases, and Merck & Co., Inc.—involved more than 38,000 veterans aged 60 and older.  The purpose was to find out how safe the vaccine is, and if it can prevent shingles. Half the study participants received the shingles vaccine, and half received a similar-looking, inactive vaccine (placebo vaccine).  Neither volunteers nor researchers knew if a particular subject had gotten an active or placebo vaccine until after the end of the study (called a double-blind study).  During more than 3 years of follow-up, the vaccine reduced shingles cases by 51 percent; 642 cases of shingles developed in the placebo group compared with only 315 in the vaccinated group.  And in people who received the active vaccine and still got shingles, the severity and discomfort were reduced by 61 percent.  The vaccine also reduced the number of cases of long-lasting nerve pain (postherpetic neuralgia) by two-thirds compared with the placebo.

The shingles vaccine is a preventive therapy and not a treatment for those who already have shingles or postherpetic neuralgia.

Chickenpox vaccine

The chickenpox vaccine became available in the United States in 1995.  Immunization with the varicella vaccine (or chickenpox vaccine)—now recommended in the United States for all children between 18 months and adolescence—can protect people from getting chickenpox.  People who have been vaccinated against chickenpox are probably less likely to get shingles because the weak, “attenuated” strain of virus used in the chickenpox vaccine is less likely to survive in the body over decades.

What is postherpetic neuralgia?

Sometimes, particularly in older people, shingles pain persists long after the rash has healed.  This is postherpetic neuralgia, defined as pain lasting three months after onset of the rash.   Pain can be mild or severe—the most severe cases can lead to insomnia, weight loss, depression, and disability. There may be other sensations, such as tingling, coldness, or loss of feeling.   About 20 percent of people age 70 or greater who develop shingles may have long-lasting pain.  Postherpetic neuralgia is not directly life-threatening and may get better over time.

About a dozen medications in four categories have been shown in clinical trials to provide some pain relief for postherpetic neuralgia. These include:

Tricyclic antidepressants (TCAs): TCAs are often the first type of drug given to people suffering from postherpetic neuralgia. The TCA amitryptiline was commonly prescribed in the past, but although effective, it has a high rate of side effects.  Desipramine and nortriptyline have fewer side effects and are therefore better choices for older adults, the most likely group to have postherpetic neuralgia.

Common side effects of TCAs include dry eyes and mouth, constipation, and impaired memory. People with heart arrhythmias (irregular heartbeats), previous heart attacks, or narrow angle glaucoma should usually use a different class of drugs.

Anticonvulsants:  Some drugs developed to reduce seizures can also treat postherpetic neuralgia because seizures and pain both involve abnormally increased firing of nerve cells.  The antiseizure medication gabapentin is most often prescribed.  Carbamazepine is effective for postherpetic neuralgia but has somewhat common side effects including drowsiness or confusion, dizziness, and sometimes ankle swelling.  Some small studies have shown positive effects using divalproex sodium to treat postherpetic neuralgia.

Opioids:  Opioids are strong pain medications used for all types of pain.  They include oxycodone, morphine, tramadol, and methadone.  Opioids can have side effects—including drowsiness, mental dulling, and constipation—and can be addictive, so their use must be monitored carefully in those with a history of addiction.

Topical local anesthetics:  Local anesthetics are effective when applied directly to the skin of the painful area affected by postherpetic neuralgia.  Lidocaine, the most commonly prescribed, is available in cream, gel, or spray form.  It is also available in a patch that has been approved by the FDA for use specifically in postherpetic neuralgia. With topical local anesthetics, the drug stays in the skin and therefore does not cause problems such as drowsiness or constipation. Capsaicin cream may be somewhat effective and is available over the counter, but most people find that it causes severe burning pain during application.  An alternative approach using a high concentration capsaicin patch has been reported to be effective.

Postherpetic itch

The itch that sometimes occurs during or after shingles can be quite severe and painful.  Clinical experience suggests that postherpetic itch is harder to treat than postherpetic neuralgia.  Topical local anesthetics (which numb the skin) provide substantial relief to some individuals.  Since postherpetic itch typically develops in the skin that has a severe sensory loss, it is particularly important to avoid scratching. Scratching numb skin too long or too hard can cause injury.

What are other complications of shingles?

Complications of zoster are more frequent in people with lesions in or around the eyes, forehead, and nose (ophthalmic shingles), or around the ear and on the face (herpes zoster oticus or Ramsay-Hunt syndrome).   People with shingles in or near the eye should see an ophthalmologist immediately, as they can suffer painful eye infections and, in some cases, temporary or permanent vision loss.  Symptoms can include redness and swelling involving just the white of the eye (sclera), the clear front of the eye (cornea), or internal parts of the eye.  If the cornea is involved, treatment to avert permanent scarring is important to preventing lasting vision loss.  The disease can cause damage to or death of the nerve cells that react to light (called acute retinal necrosis).

Shingle infections within or near the ear can cause hearing or balance problems as well as weakness of the muscles on the affected side of the face.   These problems can be long-lasting or permanent.

In rare cases, shingles can spread into the brain or spinal cord and cause serious complications such as stroke or meningitis (an infection of the membranes outside the brain and spinal cord).

The varicella-zoster virus also may involve blood vessels or provoke an immune reaction irritating the surface of blood vessels (vasculopathy).  People with shingles have a slightly increased risk of stroke, greatest in the first few weeks after vesicle eruption, but lasting for several months.  The risk of stroke is highest in people with eye zoster, perhaps as much as five percent.

People with shingles need to seek immediate medical evaluation if they notice neurological symptoms outside the region of the primary shingles attack.  People who are immunosuppressed, whether from diseases such as HIV or medications, have an increased risk of serious complications from shingles.  They may develop shingles that spread to involve more parts of the body, or shingles rashes that persist for long periods or return frequently.  Many such individuals are helped by taking antiviral medications on a continuous basis.  People taking immunosuppressive drugs, or with diseases such as HIV or leukemia, should see a doctor immediately for treatment to avoid possible serious complications.

Can infection with VZV during pregnancy harm the baby?

Some infections can be transmitted across the mother’s bloodstream to the fetus or can be acquired by the baby during the birth process.  Chickenpox during pregnancy poses some risk to the unborn child, depending upon the stage of pregnancy.  During the first 30 weeks, maternal chickenpox may, in some cases, lead to congenital malformations (although such cases are rare).  Most experts agree that shingles in a pregnant woman are even less likely to cause harm to the unborn child.

If a pregnant woman gets chickenpox between 21 to 5 days before giving birth, her newborn can have chickenpox at birth or develop it within a few days. But the time-lapse between the start of the mother’s illness and the birth of the baby generally allows the mother’s immune system to react and produce antibodies to fight the virus.  These antibodies can be transmitted to the unborn child and thus help fight the infection. Still, a small percent of the babies exposed to chickenpox in the 21 to 5 days before birth develop shingles in the first 5 years of life because the newborn’s immune system is not yet fully functional and capable of keeping the virus latent.

If a mother contracts chickenpox at the time of birth, the newborn will have little ability to fight off the attack because its immune system is immature. If these babies develop chickenpox as a result, it can be fatal. They are given zoster immune globulin, a preparation made from the antibody-rich blood of adults who have recently recovered from chickenpox or shingles, to lessen the severity of their chickenpox.

What research is being done?

The mission of the National Institute of Neurological Disorders and Stroke (NINDS) is to seek fundamental knowledge about the brain and nervous system and to use that knowledge to reduce the burden of neurological disease.  The NINDS is a component of the National Institutes of Health, the leading supporter of biomedical research in the world.

The NINDS funds and conducts research on a wide range of neurological disorders, such as shingles, to understand their causes and to develop and improve ways to diagnose, treat, and prevent them.

Medical research on shingles has two main goals.  The first is to develop drugs to fight the disease and to prevent or treat its complications.   The second is to understand the disease well enough to prevent it, especially in people at high risk.  To achieve these goals, scientists need to learn much more about VZV and its effects, including how it becomes latent in nerve cells (neurons), what induces it to become active again, and how such reactivation can lead to postherpetic neuralgia and other complications..

For example, the NINDS supports research on the interplay between the viral proteins and virus defense mechanisms in neurons to understand why the varicella-zoster virus establishes latency uniquely in neurons and not in other cell types.  Other studies focus on how VZV travels along sensory nerve fibers, or axons, and its role in latency and viral reactivation.  Scientists also hope to identify molecular mechanisms that regulate the expression of latent viral genes, which may lead to targeted therapy to prevent reactivation.

Research on postherpetic neuralgia includes studies in animal models of the condition, to better understand cellular changes that lead to persistent pain.  These changes may represent future targets in the form of improved vaccines, new medicines, or even gene therapy.

Antiviral Therapy

The oral antiviral agents’ acyclovir (Zovirax), valacyclovir (Valtrex), and famciclovir (Famvir, Novartis) have been shown to reduce the severity and duration of VZV infection, and these drugs are considered the mainstays of herpes zoster therapy.,, Topical antiviral agents are ineffective for the treatment of herpes zoster and are not recommended.

Antiviral Agents Used in the Treatment of Herpes Zoster in Immunocompetent Adults

Drug Dosage FDA Approval? Generic Version Available? Average Wholesale Price (Generic) for 7 Days of Therapy
Acyclovir (Zovirax, Valeant) 800 mg every 4 hours (five times daily) for 7 to 10 days Yes Yes $128.33
Famciclovir (Famvir, Novartis) 500 mg every 8 hours (three times daily) for 7 days Yes Yes $266.06
Valacyclovir (Valtrex, GlaxoSmithKline) 1,000 mg every 8 hours (three times daily) for 7 days Yes Yes $265.63

The earlier that antiviral therapy is initiated after the presentation of herpes zoster symptoms, the greater the likelihood of clinical response. Most trials of zoster treatments enroll patients within 72 hours after the onset of a rash; acyclovir was reported to be most effective when administered within 48 hours after rash onset. However, limiting the use of antiviral drugs to the treatment of early symptoms may deny the potential benefits of these agents to zoster patients who still require treatment after the customary 72-hour therapeutic window., In an observational study of valacyclovir, DeCriox et al. observed no difference in the duration of zoster-associate d pain and paresthesia in patients treated within 72 hours after the onset of rash and in patients treated after that period.

Acyclovir. Acyclovir is considered the “gold standard” of treatment. However, the drug’s clinical use is limited by its multiple-dosing schedule and less favorable pharmacokinetic profile compared with that of the second-generation antivirals valacyclovir and famciclovir. So far, VZV resistance to acyclovir has not been a major concern. Resistance in immunocompromised patients might be expected to increase, however.

Valacyclovir. As the oral prodrug of acyclovir, valacyclovir is a safe and effective alternative to its parent compound. A valacyclovir dose (1,000 mg three times daily for 7 or 14 days) was compared with acyclovir (800 mg five times daily for 7 days) in a randomized, double-blind study involving immunocompetent adults. Valacyclovir significantly accelerated the resolution of herpes zoster–associated pain at both 7 days compared with acyclovir. However, cutaneous manifestations resolved at similar rates with both drugs.

Famciclovir. Famciclovir, the prodrug of penciclovir, has more extensive bioavailability compared with acyclovir, and its active metabolite has a longer half-life, allowing a simpler dosing regimen (500 mg every 8 hours for 7 days vs. 800 mg five times daily for 7 to 10 days, respectively).

Shafran et al. compared famciclovir and acyclovir in immunocompetent adults in a randomized, double-blind trial. The primary efficacy endpoint was the time to full crusting of zoster lesions (i.e., lesion duration). The median times to crusting did not differ significantly between the two drugs.

In another study, famciclovir and acyclovir were clinically and statistically equivalent in terms of preventing the formation of new zoster lesions.

Foscarnet. Foscarnet (Foscavir) an organic analog of inorganic pyrophosphate, is approved only for the treatment of acyclovir-resistant herpes simplex virus. However, several case reports and small studies have described the successful treatment of VZV infection with this drug, particularly in AIDS patients. The clinical use of foscavir may be limited by its toxic effects, which include acute renal failure, gastrointestinal symptoms, genital ulcers, and seizures.

Britain. A nucleoside analog, brivudin (CAS 69304-47-8, Santa Cruz Biotechnology) is highly selective for VZV. The drug is not currently available in the U.S., but it was shown to be equivalent to famciclovir in a randomized, double-blind, multinational study. The drug’s once-daily dosing may make it the optimal choice for the treatment of herpes zoster in elderly patients.

Immunocompromised Patients. Individuals with compromised immunity are at increased risk for the development of herpes zoster. Those at greatest risk include patients with lymphoproliferative malignancies, organ transplant recipients, patients receiving systemic corticosteroids, and patients with AIDS. Intravenous (IV) acyclovir (10 mg/kg every 8 hours) remains the treatment of choice for herpes zoster in severely immunocompromised patients. IV antiviral treatment can be replaced by oral therapy after the infection is under control.

Ocular Involvement. If untreated, herpes zoster ophthalmicus can lead to chronic ocular inflammation, debilitating pain, and blindness. The most effective drugs for treating this disorder appear to be acyclovir, valacyclovir, and famciclovir. Additional management of associated symptoms, such as dry eye and glaucoma, may be warranted.

Therapy for Acute Pain

The acute pain of herpes zoster has a profound effect on health-related QOL. When clinicians consider the treatment of zoster-associated pain, however, they often focus on the chronic pain of PHN. The literature regarding the treatment of acute zoster pain is limited. Typically, narcotic analgesics, tricyclic antidepressants, nonsteroidal anti-inflammatory drugs (NSAIDs), and acetaminophen are added to antiviral therapy, with varying degrees of efficacy., The treatment of choice depends on the severity of the pain. More studies are needed to determine the most appropriate therapies for acute zoster pain.

Antiviral Therapy. Acute pain may be reduced if appropriate antiviral therapy is started within 72 hours after zoster symptoms appear, although patients will still be at risk for the development of PHN.

Analgesic Drugs. A randomized, placebo-controlled study compared controlled-release oxycodone (OxyContin, Purdue Pharma) with gabapentin (Neurontin, Pfizer) in patients with the acute pain of herpes zoster. Patients treated with oxycodone experienced significant pain relief compared with that given placebo during the first 14 days of treatment, whereas gabapentin-treated patients did not show any difference compared with the placebo group. Oral analgesics may be used to treat acute pain in zoster patients with ocular involvement. Clinicians should never instill topical anesthetics directly onto the cornea in these patients.

Opioids. Elderly patients might not be able to tolerate high doses of opioids and therefore might not achieve maximum pain control with these drugs. Kanodia et al. compared the efficacy of gabapentin and placebo in geriatric patients with acute herpetic neuralgia. Patients received 300, 600, or 900 mg of gabapentin daily. By the fourth week, pain-scale scores were significantly improved (P < 0.001) in all three treatment groups compared with the placebo group.

Corticosteroids. The use of systemic corticosteroids to treat the acute pain of herpes zoster is controversial. Articles about corticosteroid therapy in zoster patients often include recommendations based on judgment and experience rather than on clinical evidence.According to one report, corticosteroids were found to offer a slight benefit in preventing acute zoster-associated pain. However, the risks of using corticosteroids to treat herpes zoster may outweigh any potential benefits in patients with concomitant conditions that can be exacerbated by these drugs. If it is decided to begin the treatment of zoster pain with corticosteroids, they should be administered only in combination with antiviral agents., The treatment of herpes zoster with topical corticosteroids is not recommended.

Aspirin. Topical aspirin has been studied in a number of different vehicles for the treatment of acute herpetic neuralgia. Balakrishnan et al., for example, studied the effects of a compounded topical aspirin/moisturizer combination versus oral aspirin. The authors concluded that the local analgesic effect of topical aspirin in a moisturizer was superior to the analgesia achieved with oral aspirin in relieving the acute pain of herpes zoster.

Therapy for Chronic Pain

The goal of any treatment approach to herpes zoster is to prevent complications and long-term sequelae. In this regard, the early use of antiviral drugs may help to reduce the development of PHN. A literature review found little support for the use of corticosteroids for preventing PHN.

Managing the chronic pain of PHN is a complicated process, and current treatment modalities are often unsatisfactory. Studies have shown that some drugs, including analgesics, anesthetics, narcotics, tricyclic antidepressants, and anti-epileptic agents, may provide at least partial pain relief., For the effective treatmerx]nt of PHN, it may be necessary to administer drug combinations for extended periods in order to achieve sufficient relief. Further research is needed to identify effective targeted therapies.

Analgesic Drugs. Patients with mild-to-moderate PHN may benefit from acetaminophen, aspirin, or NSAIDs such as ibuprofen. These drugs rarely provide complete pain relief, however, and combination therapy with stronger analgesics may be necessary. For optimal pain control, it is important that clinicians prescribe these medications around the clock rather than as needed. Neuropathic pain, such as PHN, is generally less responsive to analgesic drugs than non-neuropathic pain.

Opioids. Experts have long debated the use of opioids in the management of chronic neuropathic pain., Data from randomized controlled trials suggest that these drugs may be useful in relieving PHN, but more studies are needed to determine their long-term benefits. Opioids may be considered for patients with moderate-to-severe PHN or with PHN-related sleep disturbances as part of a comprehensive treatment plan.

The general principles of pain control with opioids for PHN include titrating the dose to achieve optimal efficacy while reducing side effects, documenting the treatment plan and outcomes, monitoring side effects, and adding a prophylactic laxative to prevent constipation. Clinicians should use a controlled-release opioid regimen and should be prepared to provide immediate breakthrough analgesia.

The adverse effects associated with opioids, including constipation, nausea, confusion, and sedation, are of particular concern in elderly patients, and opioids should be used with caution in these individuals.

Tramadol (Ultram, Janssen), a centrally-acting opioid, has been effective in treating the pain associated with polyneuropathy. In a randomized, double-blind, placebo-controlled study, extended-release tramadol achieved a significant (P = 0.031) reduction in pain intensity compared with placebo over a 6-week period in patients with PHN. Clinicians should closely monitor the adverse effects of tramadol, which include nausea, dizziness, and constipation.

Tricyclic Antidepressants. Tricyclic antidepressants (TCAs) are widely used for the management of neuropathic pain. Early treatment with low-dose amitriptyline has been shown to reduce the pain of PHN by more than 50% compared with placebo (P < 0.05).96 Amitriptyline or its metabolite, nortriptyline (Pamelor, Mallinckrodt), appears to be the standard of care for the management of most forms of neuropathic pain. However, nortriptyline and desipramine (Norpramin, Sanofi) may be preferred over amitriptyline and imipramine (Tofranil, Mallinckrodt) because of their lower risk of adverse effects.,

The anticholinergic side effects of TCAs, such as dry mouth, drowsiness, and constipation, must be closely monitored when these drugs are administered to elderly patients.

Anticonvulsant Drugs. Because of their ability to reduce neuronal derangement, anticonvulsant drugs may be used to treat PHN. Gabapentin is a well-established therapy for neuropathic pain and has demonstrated clinical benefit in patients with PHN.,,,

Pregabalin (Lyrica, Pfizer), a newer anticonvulsant drug, has been found to be effective in treating PHN in several randomized controlled trials. Freynhagen et al. reported that both fixed-dose and flexible-dose pregabalin were significantly more effective than placebo (P = 0.002) in reducing pain scores in patients with neuropathic pain.

Dose adjustments are required for both gabapentin and pregabalin in patients at risk of renal impairment. Patients treated with either drug must be monitored for adverse effects, including dizziness, somnolence, and peripheral edema.

Topical Therapy. Elderly patients may be intolerant of oral medications that are used to manage PHN. Investigators have therefore given increased attention to topical therapies that may help to relieve the pain associated with herpes zoster.

Lidocaine. Lidocaine 5% (Lidoderm, Endo) has been administered successfully as a topical patch for the treatment of PHN, and may be considered a first-line treatment in this setting.

Piroxicam. A study conducted in Korea compared a topical piroxicam patch (Feldene, Pfizer; not approved in the U.S.) with the lidocaine patch in patients with PHN. The lidocaine patch was more effective in treating allodynia, whereas the piroxicam patch was more effective in treating dull pain. Although the results of this study did not demonstrate the clear superiority of one patch over another, more trials of this kind are needed to identify effective therapies for PHN.

Capsaicin. Capsaicin (the main capsaicinoid in chili peppers) works by desensitizing sensory nerve fibers. Topical capsaicin has proved beneficial for the treatment of neuropathic pain in a few clinical trials, but the pain relief that the drug elicits may be delayed. Moreover, adverse effects, such as stinging and burning at the application site, may limit its use, particularly in the elderly. Topical capsaicin has been approved as a patch (Qutenza, NeurogesX) for the relief of neuropathic pain associated with PHN. Up to four patches may be applied to the skin for a total of 60 minutes every 3 months.

Alternative Therapies

In response to the dose-limiting adverse effects associated with current PHN therapies, investigators have studied the clinical efficacy of complementary and alternative medicine (CAM) in reducing the pain of PHN., Alternative approaches include acupuncture, neural therapy, cupping and bleeding, meditation, and the ingestion of Chinese herbs. All of these strategies have shown some benefit in reducing pain symptoms when used in conjunction with conventional medical treatments. Although the suggested pain-relieving effects of alternative therapies have not been studied on a large scale, these approaches may offer a way to improve the quality of life of patients with PHN.

References

Actinic Cheilitis – Causes, Symptoms, Treatment

Actinic Cheilitis/Actinic Keratoses (AKs), also referred to as senile keratoses or solar keratoses, are benign intra-epithelial neoplasms and represent one of the most common skin disorders evaluated by dermatologists. Often associated with chronic sun exposure, individuals with AKs may present with irregular, red, scaly papules or plaques on sun-exposed regions of the body. If left untreated, AKs have the potential to evolve into invasive squamous cell carcinoma, which underscores the importance of early detection and development of a treatment plan. There are a variety of management options that are available for AKs, which will be covered in this review.

Another Name

  • Cheilitis,
  • actinic (Actinic cheilitis, solar cheilitis, actinic cheilosis, cheilitis actinic, cheilosis actinic, actinic keratosis of the lip, solar keratosis of the lip, cheilitis exfoliativa).

Pathophysiology

The pathophysiology of actinic keratoses development is complex. Excessive and cumulative UV radiation exposure from the sun can induce a number of pathologic changes to the epidermal keratinocyte through the disruption of regulatory pathways involved in cell growth and differentiation. The resulting inflammation and immunosuppression lead to the intraepidermal proliferation of dysplastic keratinocytes, which give rise to AKs.

Causes of Actinic Keratoses

Actinic keratoses typically develop from the damaging effects of ultraviolet (UV) radiation to the skin accumulated over a lifetime of sun exposure. Actinic keratoses are predominantly located on chronically sun-exposed areas of the body such as the face, scalp (bald or thinning), back of the arms, and dorsal aspect of the hands, especially in older people who have accumulated decades of sun exposure. There are numerous independent risk factors associated with the development of AKs, including:

  • Increased Age – AKs increasingly affect the older population due to the high cumulative lifetime exposure to the sun and inadequate sun protection.
  • Male Gender – AK prevalence is higher in men compared to women.
  • Fair-skinned individuals (Fitzpatrick Skin Phototypes I and II) – Pale or light-skinned individuals have less melanin pigment in the skin and tend to burn easily with sun exposure. Other characteristics of these skin phototypes may include red or blonde hair and blue or light-colored eyes.
  • Geographic Location – Countries located closer to the equator demonstrate higher rates of AKs. For example, prevalence rates of AKs in Australia are close to 60% due to its proximity to the equator (in addition to its sizable White population). In contrast, the prevalence of AKs in a non-equatorial location, such as the United States, is around 20%.
  • Immunosuppression – Individuals with a compromised immune system have an increased susceptibility to develop AKs, such as observed with chemotherapy, acquired immune deficiency syndrome, immunosuppressive medications (transplant medications), and leukemia.
  • History of Actinic Keratosis and/or Previous Skin Malignancy – This important component of the history may indicate genetic factors associated with increased susceptibility to UV radiation as well as the chronicity of UV radiation exposure to which the individual has been exposed.
  • Excessive and Chronic Sun Exposure – People with greater cumulative lifetime exposure to UV radiation from the sun are more prone to developing AKs. At-risk individuals include those with outdoor occupations (e.g., construction, farming) and outdoor activities (e.g., tennis, golf, baseball players).

Symptoms of Actinic Keratoses

The signs and symptoms of an actinic keratosis include:

  • A rough, dry or scaly patch of skin, usually less than 1 inch (2.5 centimeters) in diameter
  • Flat to slightly raised patch or bump on the top layer of skin
  • In some cases, a hard, wartlike surface
  • Color as varied as pink, red or brown
  • Itching or burning in the affected area

Diagnosis of Actinic Keratoses

The primary histopathologic feature of actinic keratoses is atypical keratinocytes in sun-damaged skin that is limited to the lower third of the epidermis.

History and Physical

Important elements of the patient history include

  • Presenting symptoms (pruritus, pain, bleeding with minor trauma) of the lesion(s), a thorough review of medical problems and medications, previous skin cancer treatments/surgery, and a thorough assessment of all risk factors as outlined above, including duration/history of sun exposure, history of sunburn, use of sunscreen, sun protection habits, and occupation.
  • The physical exam involves a detailed full-body skin exam with particular attention to the number, size, distribution, and description of any suspicious skin lesions or skin pathology, especially in the sun-exposed areas of the body (head, face scalp, neck, dorsal forearms, hands). The presence of any ulceration and bleeding should be noted. AKs may appear as scaly, erythematous macules, papules, plaques, or cutaneous horns. Surrounding skin changes may indicate solar damage. AKs often are better appreciated by their rough texture on palpation as they may demonstrate differing degrees of hyperkeratosis.

Evaluation

  • Evaluation of actinic keratoses is primarily by clinical observation during the physical examination. In some cases, useful diagnostic adjuncts to the clinical exam may include dermoscopy or biopsy. On dermoscopy, non-pigmented facial AKs are characterized by a strawberry pattern and include an erythematous vessel pseudo network, prominent follicular openings, and a surrounding white halo.
  • A shave or punch biopsy may be recommended in cases of diagnostic uncertainty, failure to respond to treatment, or in situations where one wants to determine whether an AK has progressed to squamous cell carcinoma.

Treatment

Dermatologists often recommend treatment, long-term follow-up, and preventive strategies to reduce symptomatic actinic keratoses, as well as development and progression to squamous cell carcinoma. The average risk for malignant transformation is 8% in immunocompetent patients, with a range from 0.025% to 16%.

Although there are a variety of options available for the treatment of AKs, the treatment mantra is the same: “no pain, no gain.” Lesion-directed therapies (e.g., cryotherapy, curettage, surgery) target individual AKs, whereas field-directed therapies (e.g., topical medications, light-based therapies, laser resurfacing) have the advantage of treating multiple, widespread, and subclinical AKs that may be within a field of chronic sun damage.

Treatment strategies should be individualized, taking into account several factors: AK’s characteristics and symptoms, patient desires/expectations, treatment availability, patient’s ability to comply with treatment regimens, tolerability of treatment side effects, and cost. Urgency is indicated when lesions are numerous, bleeding, painful, and/or rapidly growing in size. The timeline of expected side effects of blistering, erosion, crusting, burning, discomfort, pain, pruritus, erythema, and edema must be reviewed, as well as how to care for the skin as it heals, regenerates, and recovers from the treatment.

No treatment is without risks. All AK treatments may result in the following potential adverse effects: pain, inflammation, healing issues, pigment changes, and scarring. Recurrence and need for more than one treatment are not uncommon. Healing may take days to weeks, depending on location and number of lesions treated. AKs that fail to respond to aggressive treatment should prompt consideration of treatment noncompliance, misdiagnosis, and possible malignant transformation to squamous cell carcinoma.

AKs are a cutaneous manifestation of repeated sun exposure. Patients diagnosed with AKs should undergo skin cancer screening. Photoprotection strategies and self-skin cancer surveillance should be reviewed with these individuals. Vitamin B3 dosed at 500 mg twice a day has been shown to reduce the number of AKs after several months of use.

Lesion-Directed Treatments: Target individual AKs

  • Cryotherapy – Cryotherapy is a commonly used lesion-directed treatment modality for AKs. It involves the freezing of skin lesions through the topical application of liquid nitrogen via spray or cotton tip applicator. With excellent response rates, it is a viable treatment option for patients with only a few AKs or isolated lesions. Healing will depend on the duration of liquid nitrogen application and the number of freeze-thaw cycles.
  • Curettage or Shave – Lesion removal with a curette or blade can be used for hyperkeratotic AKs that may be unresponsive to alternative treatments. Curettage or shave allows specimen collection for histopathologic evaluation. Electrodessication can be added following curettage to assist with hemostasis.
  • Chemical peel – This is a medical-grade chemical peel used to destroy the top layers of skin. You cannot get this type of chemical peel at a salon or from a kit sold for home use. After a medical-grade chemical peel, the treated skin will be red, swollen, and sore. As the area heals, you will see new healthy skin.
  • Curettage – If you have an extremely thick AK, this may the best treatment. During this procedure, your dermatologist first scrapes the AK from your skin, using a technique called curettage. Your dermatologist may follow this with an electrodesiccation, which heats the treated area to destroy any remaining AK cells.
  • Laser resurfacing – This may be a treatment option for actinic cheilitis, a precancerous growth on the lip. It works by removing the surface layer of the skin. After treatment, the skin will feel raw and sore. When it heals in 1 or 2 weeks, you see new, healthier skin.
  • Chemotherapy. A topical cancer medicinal cream called fluorouracil is applied to the skin lesion or the entire sun-damaged area. It takes around 4 to 6 weeks to work. Usually, the skin turns red and blisters before new skin appears.
  • Photodynamic therapy –  A chemical is applied to the skin. Then the skin is exposed to a light that activates the chemical to destroy the abnormal skin cells. There can be burning, stinging, and changes in pigmentation of the skin.
  • Chemical peel – A chemical solution is applied to the skin to cause blistering and peeling away of the actinic keratoses. Temporary redness and swelling will likely occur.
  • Dermabrasion – This uses a handheld device to “sand” the skin and improve its appearance. It can be used to treat large lesions that are often too big to treat with topical treatments. It leaves the skin red and raw and can be a painful procedure. A topical numbing ointment, nerve blocks, or other pain medications are often used.
  • Immunomodulator therapy – Imiquimod cream, ingenol gel, or diclofenac gel works much like fluorouracil to selectively rid the skin of abnormal cells. There may be redness, itching, swelling, crusting, and peeling

At-home treatment for actinic keratosis

If you have many AKs or AKs that you can feel but not see, your dermatologist may recommend at-home treatment.

  • When you treat at home, you apply medication to your skin as directed.
  • The advantage of using a medication to treat your AKs is that the medication can treat many AKs, including the ones you cannot see yet. Using this approach can reduce your risk of developing new AKs and possibly skin cancer.
  • The downside of applying medication to your skin is that some patients say it’s difficult to follow the treatment plan. To be effective, you need to apply the medication as often as your dermatologist recommends. Even when the medication causes a skin reaction, which indicates that it’s working, you’ll need to keep applying the medication.
  • The medications that dermatologists prescribe include the following, which have all been approved by the US. Food and Drug Administration (FDA) to treat AKs:
  • 5-fluorouracil (5-FU) cream – You apply this once or twice a day for 2 to 4 weeks. It’s often a treatment option for the chest, arms, or back, but usually not the face due to the skin reaction it causes. This is not a treatment option for a woman who is pregnant. 5-FU can harm an unborn baby.
  • Diclofenac sodium gel – This medication tends to cause less of a skin reaction than 5-FU, but it can still be very effective. You will need to apply it twice a day for 2 to 3 months. While using this medication, you must protect your treated skin from the sun. Your dermatologist can tell you the best way to protect your skin.
  • Imiquimod cream – This can be a good option for the face because you can apply it once (or twice) a week, so you don’t get lots of redness and crusting. You may need to apply it for 12 to 16 weeks. If 12 to 16 weeks is too long, you may be able to use the medication a bit differently. You’d apply imiquimod every night for 2 weeks. For the next 2 weeks, you’d give your skin a break. Then you’d apply it again, using it every night for 2 weeks.
  • Ingenol mebutate gel – This requires the shortest treatment time. To treat your face or scalp, you’d apply it for 3 days. On other parts of your body, you’d apply it for 2 days. While you apply this medication for the least amount of time, your skin will still react. For 1 or 2 weeks, you may have a reaction on your face or scalp, such as redness, swelling, crusting, or scaly skin. Reactions can last for up to 4 weeks on the other parts of your body.

Surgery

Surgical excision can be considered when the diagnosis is unclear or if there is a high suspicion of squamous cell carcinoma. Surgical excision will yield tissue for histopathologic diagnosis and help guide further treatment.

  • Surgical removal and biopsy The lesion may be removed and examined if there is a possibility it has become cancerous.
  • Field-Directed Treatments – Treat multiple, widespread, and subclinical AKs that may be within a field of chronic sun damage
  • Dermabrasion – In dermabrasion, a motorized handheld device with attached abrasive material is used to remove the superficial skin layers in areas of actinic damage.
  • Laser – Ablative resurfacing lasers (e.g., CO2 and erbium-YAG lasers) can be used to treat AKs by ablating the epidermis and superficial dermis.
  • Chemical Peels – Chemical peels have been used to treat patients with multiple or widespread facial AKs. A chemical peel involves the topical application of a caustic agent, such as trichloroacetic acid (TCA), to remove the outer skin layers to variable depths. The depth of the peel depends on the agent used, its concentration, and the duration of application. Peels for AKs are approximately 75% effective.
  • Photodynamic Therapy (PDT) – PDT involves the topical application of a photosensitizer to the treatment area and exposure to a light source of a specified wavelength, depending on the depth of skin penetration desired. The generation of reactive oxygen species leads to the destruction of atypical keratinocytes. PDT therapy is an office-based treatment. Disadvantages of conventional PDT include patient complaints of pain, extended time spent in the office during treatment sessions as well as frequent office visits for treatment. These drawbacks have prompted the development of alternative uses of PDT, including daylight photodynamic therapy, where natural daylight is used to activate the photosensitizer in place of an artificial light source. Daylight PDT reportedly has a similar lesion response rate compared to conventional PDT with the advantages of less patient discomfort and added convenience of treatment outside of the office setting.
  • Topical Medications – There are several FDA-approved topical medications for the treatment of AKs. Because the patient at home can apply these medications, patient education is imperative to obtain a favorable outcome and compliance with recommended treatment. The timeline of expected side effects of blistering, erosion, crusting, burning, discomfort, pain, pruritus, erythema, and edema must be reviewed, as well as how to care for the skin at home as it heals and recovers from the field treatment. Numerous treatment regimens have been reported for each of the drugs.
  • 5-Fluorouracil (5-FU) – 5-FU is an FDA-approved topical medication and applied one to two times per day for several weeks. 5-FU, a pyrimidine analog, acts by blocking DNA synthesis and disrupting cell division, providing some of the most effective treatment for AKs.
  • Imiquimod (IMQ) – IMQ is an FDA-approved treatment for AKs. IMQ functions to augment the patient’s immune response at the site of medicine application. It is typically indicated in limited areas of the face and scalp over several weeks.
  • Diclofenac Sodium (DFS) – DFS gel is a topical, non-steroidal, anti-inflammatory FDA-approved drug for AK treatment. The treatment regimen involves application two times per day over a course of two to three months. DFS treatment appears to be better tolerated by patients compared to 5-FU because of milder adverse skin effects.
  • Ingenol mebutate (IM) – IM is obtained from the Euphorbia peplus plant and is FDA-approved for the treatment of AKs. The mechanism of action involves rapid induction of keratinocyte cell death within a few hours and an inflammatory response over the ensuing days, which is immunostimulatory. An advantage of IM treatment is that the duration of therapy is only a couple of days, thus significantly shorter than the other topical drug treatments.

Ablative-surgical treatments

Curettage

  • The use of curettage under local anesthesia for treatment of actinic keratoses can be performed in isolation or in association with electrodesiccation, which appears to increase the resolution of potential remaining dysplastic cells and also to achieve hemostasis. An alternative to electrodesiccation is cryotherapy. As a monotherapy, a curettage is especially indicated for patients with few lesions, especially hyperkeratotic actinic keratoses. The method is frequently used in the setting of patients with large clinical variability of keratoses as a complementary therapy for lesions resistant to field cancerization therapy, in addition to allowing the collection of material for histopathological analysis.
  • Disadvantages regarding the method include the need for local anesthesia, the healing time, which can be prolonged when lesions are treated especially in the lower limbs, and the risk of dyspigmentation symptoms in the treated area., Although curettage is widely performed in daily practice, the lack of randomized clinical trials evaluating the subject results in a low degree of the recommendation of the procedure for actinic keratoses treatment.

CO2 laser

  • Lasers induce coagulative necrosis, ablation, and hyperthermia, which lead to lesional destruction. A single session of non-fractional CO2 laser could be used to remove superficial lesions on the epidermis, such as actinic keratoses. The 10,600 nm CO2 non-fractional laser has a wavelength absorbed by water, resulting in non-specific tissue destruction. Therefore, the non-fractional CO2 laser can be used for field cancerization treatment or for localized lesion destruction.
  • For localized lesions, complete lesion clearance results in the first months are similar to those obtained with cryotherapy (72.8% in the laser group vs. 78% for cryotherapy); however, in long-term follow-up, lesions treated with CO2 laser present lower sustained response rates: only 37% of the patients treated with laser remain without lesions vs. 66.8% of those treated with cryotherapy. Furthermore, because the technique is operator-dependent, different levels of expertise with the technique may influence the results. In addition, there is a risk of secondary infection, esthetical scars, and dyschromia.
  • Because of the increased risk of infection in immunosuppressed patients, the CO2 laser is not recommended for the treatment of field cancerization and should be used only for localized lesions in these patients. Although the use of CO2 laser can be considered as an option for actinic keratoses treatment, the degree of recommendation for its use in immunocompetent patients is weak.

Prevention

Topical retinoids

One of the first studies to report the benefits of topical retinoids for patients with actinic keratoses dates back to 1970, a case series of 60 patients that reported benefits of tretinoin use at 0.1–0.3%, for a reduction in actinic keratoses scores of about 50%. Subsequent studies have shown that tretinoin at a lower concentration (0.05%) was not as effective, with a maximum reduction in the number of actinic keratoses of 45%., However, despite these initial positive results, more recent studies evaluating the use of topical retinoids in a larger sample (>1000 individuals) have not been able to demonstrate their efficacy in reducing the occurrence of SCC and basal cell carcinoma (BCC) in patients at risk; besides, no benefit in reducing the number of actinic keratoses was observed.,

Serial peelings

Some studies have described the effect of serial peelings with glycolic acid, trichloroacetic acid (TCA), and salicylic acid in animal models previously exposed to UV radiation; they observed reduction of mutated p53 and expression of COX-2 mRNA, demonstrating a possible role in tumor prevention., , In humans, there are few studies with a high level of evidence on the subject. A split-face study including 15 patients with facial actinic keratoses a single session of Jessner’s peel plus TCA 35% achieved similar effectiveness to the use of 5-FU twice daily for three weeks. There was a reduction of 75% in the total number of lesions in both groups, in addition to a similar reduction between treatments in keratinocytes atypia, parakeratosis, hyperkeratosis, and inflammation in the histopathological analysis.

More recently, the association of glycolic acid or Jessner’s peel with 5-FU 5% at fortnightly intervals demonstrated effectiveness for treatment of field cancerization; 31 patients were submitted to the sessions until complete lesion remission or until completing ten sessions. The treatment was effective and showed good tolerability; moreover, only five patients presented relapses after 36 months of follow-up.

Oral retinoids

Oral retinoids, synthetic derivatives of vitamin A, are used for chemoprevention of NMSC in high-risk patients for both immunocompetent and immunosuppressed patients, including patients with genodermatoses, such as xeroderma pigmentosum., The main medications described in the studies are acitretin, etretinate, and isotretinoin; among them, acitretin has the greatest degree of evidence regarding its protective effect. Several mechanisms of action are proposed to explain the chemopreventive effect of retinoids, including immunomodulation, apoptosis, promotion of cell differentiation, and inhibition of keratinization and cell proliferation. The first randomized clinical trial evaluating the use of 5 mg etretinate three times a week in 100 patients with actinic keratoses for a period of two months observed complete or partial remission of actinic keratoses in 84% of the treated patients (37 of 44 patients) vs. 5% (2 of 42 patients) in the placebo group.

Another clinical trial with acitretin 30 mg daily for six months in 44 transplant recipients patients observed a 13.4% reduction in actinic keratoses in the treated group vs. an increase of 28.2% in the number of actinic keratoses in the placebo group. In addition, there was a reduction in the appearance of new SCCs in the acitretin group: only two of the 19 patients in the intervention group (11%) developed SCCs vs. nine of the 19 patients of the placebo group (47%) (the relative risk reduction of developing SCCs was of 78% for patients taking acitretin)., Smit et al. evaluated the use of acitretin 0.4 mg/kg/day for three months in 33 renal transplant recipients and performed the histological and immunohistochemical analysis; modifications observed in actinic keratoses were the reduction of an epidermal thickness (p < 0.002) and normalization of the K10 keratinization pattern (p < 0.02). However, there was no change in cell proliferation, which could explain the early recurrence of actinic keratoses after acitretin discontinuation. Data on the optimal dose and duration of treatment are not defined in the literature.

Oral nicotinamide

Nicotinamide, the amide form of vitamin B3, is a cofactor for ATP production that prevents ATP depletion and glycolytic blockade induced by UV radiation, and thus assists in DNA repair. In addition, nicotinamide reduces UV-induced immunosuppression without altering basal immunity. Studies for the prevention of actinic keratoses are sparse, and its use for this purpose is still debated.

The use of nicotinamide as a chemoprotective agent to reduce the appearance of new lesions of NMSC and actinic keratoses in high-risk patients, a 1 g daily dose of the medication divided into two doses, was considered effective. After 12 months of follow-up, the rates of onset of new lesions in the patients receiving nicotinamide were 23% lower compared to the placebo group (p = 0.02), with reduction of both new basal cell carcinomas (20% reduction) and SCCs (30% reduction), as well as actinic keratoses (13%). The protective effect was maintained only during the use of the medication, which presented a good safety profile. However, subsequent studies are needed to confirm the reproducibility of the beneficial effects found, as well as the appropriate treatment duration.

Photoprotection

All patients with actinic keratosis should be advised regarding physical photoprotection and the use of sunscreens as an adjuvant to the treatment, and to prevent the onset of new lesions, regardless of the type of treatment proposed.,  Regular use of sunscreen with a sun protection factor (SPF) over 15 reduces the development of new actinic keratoses in immunocompetent patients, ranging from a 50% reduction in the number of new lesions in one year (study using SPF 29) and 37% in two years (study using SPF 16) (p < 0.05)., In addition, patients who benefit the most from sunscreen use to slow the development of new actinic keratoses include young patients who have not had previous NMSC and those who tan after sunbathing (phototypes ≥III). For immunocompromised patients, a case-control study with 120 immunosuppressed patients followed for 24 months observed that the use of broad-spectrum SPF 50 sunscreen significantly reduced the appearance of new lesions in the intervention group (p < 0.05). Moreover, the effect of daily sunscreen use on spontaneous regression of actinic keratoses is also observed in both immunocompetent and immunosuppressed patients; this regression is higher than that observed in the lesions of patients who do not use sunscreen., , , In addition, the daily use of sunscreen reduces the incidence of new SCCs (p < 0.01).,

Prevention of actinic keratoses is important because the condition can precede cancer or be an early form of skin cancer. Sun safety is necessary to help prevent the development and recurrence of actinic keratosis patches and spots.

Take these steps to protect your skin from the sun:

  • Limit your time in the sun – Especially avoid time in the sun between 10 a.m. and 2 p.m. And avoid staying in the sun so long that you get sunburn or a suntan. Both result in skin damage that can increase your risk of developing actinic keratoses and skin cancer. Sun exposure accumulated over time may also cause actinic keratoses.
  • Use sunscreen. Daily use of sunscreen reduces the development of actinic keratoses. Before spending time outdoors, apply a broad-spectrum sunscreen with a sun protection factor (SPF) of at least 30. The American Academy of Dermatology recommends using a broad-spectrum, water-resistant sunscreen with an SPF of at least 30. Use sunscreen on all exposed skin, and use a lip balm with sunscreen on your lips. Apply sunscreen 15 minutes before sun exposure and reapply it every two hours — or more often if you’re swimming or perspiring.
  • Cover up – For extra protection from the sun, wear tightly woven clothing that covers your arms and legs. Also wear a broad-brimmed hat, which provides more protection than does a baseball cap or golf visor. You might also consider wearing clothing or outdoor gear specially designed to provide sun protection.
  • Avoid tanning beds – The UV exposure from a tanning bed can cause just as much skin damage as a tan acquired from the sun.
  • Check your skin regularly and report changes to your doctor – Examine your skin regularly, looking for the development of new skin growths or changes in existing moles, freckles, bumps, and birthmarks. With the help of mirrors, check your face, neck, ears, and scalp. Examine the tops and undersides of your arms and hands.

References

Actinic Keratosis of Lip – Causes, Symptoms, Treatment

Actinic Keratosis of Lip/Actinic Keratoses (AKs), also referred to as senile keratoses or solar keratoses, are benign intra-epithelial neoplasms and represent one of the most common skin disorders evaluated by dermatologists. Often associated with chronic sun exposure, individuals with AKs may present with irregular, red, scaly papules or plaques on sun-exposed regions of the body. If left untreated, AKs have the potential to evolve into invasive squamous cell carcinoma, which underscores the importance of early detection and development of a treatment plan. There are a variety of management options that are available for AKs, which will be covered in this review.

Another Name

  • Cheilitis,
  • actinic (Actinic cheilitis, solar cheilitis, actinic cheilosis, cheilitis actinic, cheilosis actinic, actinic keratosis of the lip, solar keratosis of the lip, cheilitis exfoliativa).

Pathophysiology

The pathophysiology of actinic keratoses development is complex. Excessive and cumulative UV radiation exposure from the sun can induce a number of pathologic changes to the epidermal keratinocyte through the disruption of regulatory pathways involved in cell growth and differentiation. The resulting inflammation and immunosuppression lead to the intraepidermal proliferation of dysplastic keratinocytes, which give rise to AKs.

Causes of Actinic Keratoses

Actinic keratoses typically develop from the damaging effects of ultraviolet (UV) radiation to the skin accumulated over a lifetime of sun exposure. Actinic keratoses are predominantly located on chronically sun-exposed areas of the body such as the face, scalp (bald or thinning), back of the arms, and dorsal aspect of the hands, especially in older people who have accumulated decades of sun exposure. There are numerous independent risk factors associated with the development of AKs, including:

  • Increased Age – AKs increasingly affect the older population due to the high cumulative lifetime exposure to the sun and inadequate sun protection.
  • Male Gender – AK prevalence is higher in men compared to women.
  • Fair-skinned individuals (Fitzpatrick Skin Phototypes I and II) – Pale or light-skinned individuals have less melanin pigment in the skin and tend to burn easily with sun exposure. Other characteristics of these skin phototypes may include red or blonde hair and blue or light-colored eyes.
  • Geographic Location – Countries located closer to the equator demonstrate higher rates of AKs. For example, prevalence rates of AKs in Australia are close to 60% due to its proximity to the equator (in addition to its sizable White population). In contrast, the prevalence of AKs in a non-equatorial location, such as the United States, is around 20%.
  • Immunosuppression – Individuals with a compromised immune system have an increased susceptibility to develop AKs, such as observed with chemotherapy, acquired immune deficiency syndrome, immunosuppressive medications (transplant medications), and leukemia.
  • History of Actinic Keratosis and/or Previous Skin Malignancy – This important component of the history may indicate genetic factors associated with increased susceptibility to UV radiation as well as the chronicity of UV radiation exposure to which the individual has been exposed.
  • Excessive and Chronic Sun Exposure – People with greater cumulative lifetime exposure to UV radiation from the sun are more prone to developing AKs. At-risk individuals include those with outdoor occupations (e.g., construction, farming) and outdoor activities (e.g., tennis, golf, baseball players).

Symptoms of Actinic Keratoses

The signs and symptoms of an actinic keratosis include:

  • A rough, dry or scaly patch of skin, usually less than 1 inch (2.5 centimeters) in diameter
  • Flat to slightly raised patch or bump on the top layer of skin
  • In some cases, a hard, wartlike surface
  • Color as varied as pink, red or brown
  • Itching or burning in the affected area

Diagnosis of Actinic Keratoses

The primary histopathologic feature of actinic keratoses is atypical keratinocytes in sun-damaged skin that is limited to the lower third of the epidermis.

History and Physical

Important elements of the patient history include

  • Presenting symptoms (pruritus, pain, bleeding with minor trauma) of the lesion(s), a thorough review of medical problems and medications, previous skin cancer treatments/surgery, and a thorough assessment of all risk factors as outlined above, including duration/history of sun exposure, history of sunburn, use of sunscreen, sun protection habits, and occupation.
  • The physical exam involves a detailed full-body skin exam with particular attention to the number, size, distribution, and description of any suspicious skin lesions or skin pathology, especially in the sun-exposed areas of the body (head, face scalp, neck, dorsal forearms, hands). The presence of any ulceration and bleeding should be noted. AKs may appear as scaly, erythematous macules, papules, plaques, or cutaneous horns. Surrounding skin changes may indicate solar damage. AKs often are better appreciated by their rough texture on palpation as they may demonstrate differing degrees of hyperkeratosis.

Evaluation

  • Evaluation of actinic keratoses is primarily by clinical observation during the physical examination. In some cases, useful diagnostic adjuncts to the clinical exam may include dermoscopy or biopsy. On dermoscopy, non-pigmented facial AKs are characterized by a strawberry pattern and include an erythematous vessel pseudo network, prominent follicular openings, and a surrounding white halo.
  • A shave or punch biopsy may be recommended in cases of diagnostic uncertainty, failure to respond to treatment, or in situations where one wants to determine whether an AK has progressed to squamous cell carcinoma.

Treatment

Dermatologists often recommend treatment, long-term follow-up, and preventive strategies to reduce symptomatic actinic keratoses, as well as development and progression to squamous cell carcinoma. The average risk for malignant transformation is 8% in immunocompetent patients, with a range from 0.025% to 16%.

Although there are a variety of options available for the treatment of AKs, the treatment mantra is the same: “no pain, no gain.” Lesion-directed therapies (e.g., cryotherapy, curettage, surgery) target individual AKs, whereas field-directed therapies (e.g., topical medications, light-based therapies, laser resurfacing) have the advantage of treating multiple, widespread, and subclinical AKs that may be within a field of chronic sun damage.

Treatment strategies should be individualized, taking into account several factors: AK’s characteristics and symptoms, patient desires/expectations, treatment availability, patient’s ability to comply with treatment regimens, tolerability of treatment side effects, and cost. Urgency is indicated when lesions are numerous, bleeding, painful, and/or rapidly growing in size. The timeline of expected side effects of blistering, erosion, crusting, burning, discomfort, pain, pruritus, erythema, and edema must be reviewed, as well as how to care for the skin as it heals, regenerates, and recovers from the treatment.

No treatment is without risks. All AK treatments may result in the following potential adverse effects: pain, inflammation, healing issues, pigment changes, and scarring. Recurrence and need for more than one treatment are not uncommon. Healing may take days to weeks, depending on location and number of lesions treated. AKs that fail to respond to aggressive treatment should prompt consideration of treatment noncompliance, misdiagnosis, and possible malignant transformation to squamous cell carcinoma.

AKs are a cutaneous manifestation of repeated sun exposure. Patients diagnosed with AKs should undergo skin cancer screening. Photoprotection strategies and self-skin cancer surveillance should be reviewed with these individuals. Vitamin B3 dosed at 500 mg twice a day has been shown to reduce the number of AKs after several months of use.

Lesion-Directed Treatments: Target individual AKs

  • Cryotherapy – Cryotherapy is a commonly used lesion-directed treatment modality for AKs. It involves the freezing of skin lesions through the topical application of liquid nitrogen via spray or cotton tip applicator. With excellent response rates, it is a viable treatment option for patients with only a few AKs or isolated lesions. Healing will depend on the duration of liquid nitrogen application and the number of freeze-thaw cycles.
  • Curettage or Shave – Lesion removal with a curette or blade can be used for hyperkeratotic AKs that may be unresponsive to alternative treatments. Curettage or shave allows specimen collection for histopathologic evaluation. Electrodessication can be added following curettage to assist with hemostasis.
  • Chemical peel – This is a medical-grade chemical peel used to destroy the top layers of skin. You cannot get this type of chemical peel at a salon or from a kit sold for home use. After a medical-grade chemical peel, the treated skin will be red, swollen, and sore. As the area heals, you will see new healthy skin.
  • Curettage – If you have an extremely thick AK, this may the best treatment. During this procedure, your dermatologist first scrapes the AK from your skin, using a technique called curettage. Your dermatologist may follow this with an electrodesiccation, which heats the treated area to destroy any remaining AK cells.
  • Laser resurfacing – This may be a treatment option for actinic cheilitis, a precancerous growth on the lip. It works by removing the surface layer of the skin. After treatment, the skin will feel raw and sore. When it heals in 1 or 2 weeks, you see new, healthier skin.
  • Chemotherapy. A topical cancer medicinal cream called fluorouracil is applied to the skin lesion or the entire sun-damaged area. It takes around 4 to 6 weeks to work. Usually, the skin turns red and blisters before new skin appears.
  • Photodynamic therapy –  A chemical is applied to the skin. Then the skin is exposed to a light that activates the chemical to destroy the abnormal skin cells. There can be burning, stinging, and changes in pigmentation of the skin.
  • Chemical peel – A chemical solution is applied to the skin to cause blistering and peeling away of the actinic keratoses. Temporary redness and swelling will likely occur.
  • Dermabrasion – This uses a handheld device to “sand” the skin and improve its appearance. It can be used to treat large lesions that are often too big to treat with topical treatments. It leaves the skin red and raw and can be a painful procedure. A topical numbing ointment, nerve blocks, or other pain medications are often used.
  • Immunomodulator therapy – Imiquimod cream, ingenol gel, or diclofenac gel works much like fluorouracil to selectively rid the skin of abnormal cells. There may be redness, itching, swelling, crusting, and peeling

At-home treatment for actinic keratosis

If you have many AKs or AKs that you can feel but not see, your dermatologist may recommend at-home treatment.

  • When you treat at home, you apply medication to your skin as directed.
  • The advantage of using a medication to treat your AKs is that the medication can treat many AKs, including the ones you cannot see yet. Using this approach can reduce your risk of developing new AKs and possibly skin cancer.
  • The downside of applying medication to your skin is that some patients say it’s difficult to follow the treatment plan. To be effective, you need to apply the medication as often as your dermatologist recommends. Even when the medication causes a skin reaction, which indicates that it’s working, you’ll need to keep applying the medication.
  • The medications that dermatologists prescribe include the following, which have all been approved by the US. Food and Drug Administration (FDA) to treat AKs:
  • 5-fluorouracil (5-FU) cream – You apply this once or twice a day for 2 to 4 weeks. It’s often a treatment option for the chest, arms, or back, but usually not the face due to the skin reaction it causes. This is not a treatment option for a woman who is pregnant. 5-FU can harm an unborn baby.
  • Diclofenac sodium gel – This medication tends to cause less of a skin reaction than 5-FU, but it can still be very effective. You will need to apply it twice a day for 2 to 3 months. While using this medication, you must protect your treated skin from the sun. Your dermatologist can tell you the best way to protect your skin.
  • Imiquimod cream – This can be a good option for the face because you can apply it once (or twice) a week, so you don’t get lots of redness and crusting. You may need to apply it for 12 to 16 weeks. If 12 to 16 weeks is too long, you may be able to use the medication a bit differently. You’d apply imiquimod every night for 2 weeks. For the next 2 weeks, you’d give your skin a break. Then you’d apply it again, using it every night for 2 weeks.
  • Ingenol mebutate gel – This requires the shortest treatment time. To treat your face or scalp, you’d apply it for 3 days. On other parts of your body, you’d apply it for 2 days. While you apply this medication for the least amount of time, your skin will still react. For 1 or 2 weeks, you may have a reaction on your face or scalp, such as redness, swelling, crusting, or scaly skin. Reactions can last for up to 4 weeks on the other parts of your body.

Surgery

Surgical excision can be considered when the diagnosis is unclear or if there is a high suspicion of squamous cell carcinoma. Surgical excision will yield tissue for histopathologic diagnosis and help guide further treatment.

  • Surgical removal and biopsy The lesion may be removed and examined if there is a possibility it has become cancerous.
  • Field-Directed Treatments – Treat multiple, widespread, and subclinical AKs that may be within a field of chronic sun damage
  • Dermabrasion – In dermabrasion, a motorized handheld device with attached abrasive material is used to remove the superficial skin layers in areas of actinic damage.
  • Laser – Ablative resurfacing lasers (e.g., CO2 and erbium-YAG lasers) can be used to treat AKs by ablating the epidermis and superficial dermis.
  • Chemical Peels – Chemical peels have been used to treat patients with multiple or widespread facial AKs. A chemical peel involves the topical application of a caustic agent, such as trichloroacetic acid (TCA), to remove the outer skin layers to variable depths. The depth of the peel depends on the agent used, its concentration, and the duration of application. Peels for AKs are approximately 75% effective.
  • Photodynamic Therapy (PDT) – PDT involves the topical application of a photosensitizer to the treatment area and exposure to a light source of a specified wavelength, depending on the depth of skin penetration desired. The generation of reactive oxygen species leads to the destruction of atypical keratinocytes. PDT therapy is an office-based treatment. Disadvantages of conventional PDT include patient complaints of pain, extended time spent in the office during treatment sessions as well as frequent office visits for treatment. These drawbacks have prompted the development of alternative uses of PDT, including daylight photodynamic therapy, where natural daylight is used to activate the photosensitizer in place of an artificial light source. Daylight PDT reportedly has a similar lesion response rate compared to conventional PDT with the advantages of less patient discomfort and added convenience of treatment outside of the office setting.
  • Topical Medications – There are several FDA-approved topical medications for the treatment of AKs. Because the patient at home can apply these medications, patient education is imperative to obtain a favorable outcome and compliance with recommended treatment. The timeline of expected side effects of blistering, erosion, crusting, burning, discomfort, pain, pruritus, erythema, and edema must be reviewed, as well as how to care for the skin at home as it heals and recovers from the field treatment. Numerous treatment regimens have been reported for each of the drugs.
  • 5-Fluorouracil (5-FU) – 5-FU is an FDA-approved topical medication and applied one to two times per day for several weeks. 5-FU, a pyrimidine analog, acts by blocking DNA synthesis and disrupting cell division, providing some of the most effective treatment for AKs.
  • Imiquimod (IMQ) – IMQ is an FDA-approved treatment for AKs. IMQ functions to augment the patient’s immune response at the site of medicine application. It is typically indicated in limited areas of the face and scalp over several weeks.
  • Diclofenac Sodium (DFS) – DFS gel is a topical, non-steroidal, anti-inflammatory FDA-approved drug for AK treatment. The treatment regimen involves application two times per day over a course of two to three months. DFS treatment appears to be better tolerated by patients compared to 5-FU because of milder adverse skin effects.
  • Ingenol mebutate (IM) – IM is obtained from the Euphorbia peplus plant and is FDA-approved for the treatment of AKs. The mechanism of action involves rapid induction of keratinocyte cell death within a few hours and an inflammatory response over the ensuing days, which is immunostimulatory. An advantage of IM treatment is that the duration of therapy is only a couple of days, thus significantly shorter than the other topical drug treatments.

Ablative-surgical treatments

Curettage

  • The use of curettage under local anesthesia for treatment of actinic keratoses can be performed in isolation or in association with electrodesiccation, which appears to increase the resolution of potential remaining dysplastic cells and also to achieve hemostasis. An alternative to electrodesiccation is cryotherapy. As a monotherapy, a curettage is especially indicated for patients with few lesions, especially hyperkeratotic actinic keratoses. The method is frequently used in the setting of patients with large clinical variability of keratoses as a complementary therapy for lesions resistant to field cancerization therapy, in addition to allowing the collection of material for histopathological analysis.
  • Disadvantages regarding the method include the need for local anesthesia, the healing time, which can be prolonged when lesions are treated especially in the lower limbs, and the risk of dyspigmentation symptoms in the treated area., Although curettage is widely performed in daily practice, the lack of randomized clinical trials evaluating the subject results in a low degree of the recommendation of the procedure for actinic keratoses treatment.

CO2 laser

  • Lasers induce coagulative necrosis, ablation, and hyperthermia, which lead to lesional destruction. A single session of non-fractional CO2 laser could be used to remove superficial lesions on the epidermis, such as actinic keratoses. The 10,600 nm CO2 non-fractional laser has a wavelength absorbed by water, resulting in non-specific tissue destruction. Therefore, the non-fractional CO2 laser can be used for field cancerization treatment or for localized lesion destruction.
  • For localized lesions, complete lesion clearance results in the first months are similar to those obtained with cryotherapy (72.8% in the laser group vs. 78% for cryotherapy); however, in long-term follow-up, lesions treated with CO2 laser present lower sustained response rates: only 37% of the patients treated with laser remain without lesions vs. 66.8% of those treated with cryotherapy. Furthermore, because the technique is operator-dependent, different levels of expertise with the technique may influence the results. In addition, there is a risk of secondary infection, esthetical scars, and dyschromia.
  • Because of the increased risk of infection in immunosuppressed patients, the CO2 laser is not recommended for the treatment of field cancerization and should be used only for localized lesions in these patients. Although the use of CO2 laser can be considered as an option for actinic keratoses treatment, the degree of recommendation for its use in immunocompetent patients is weak.

Prevention

Topical retinoids

One of the first studies to report the benefits of topical retinoids for patients with actinic keratoses dates back to 1970, a case series of 60 patients that reported benefits of tretinoin use at 0.1–0.3%, for a reduction in actinic keratoses scores of about 50%. Subsequent studies have shown that tretinoin at a lower concentration (0.05%) was not as effective, with a maximum reduction in the number of actinic keratoses of 45%., However, despite these initial positive results, more recent studies evaluating the use of topical retinoids in a larger sample (>1000 individuals) have not been able to demonstrate their efficacy in reducing the occurrence of SCC and basal cell carcinoma (BCC) in patients at risk; besides, no benefit in reducing the number of actinic keratoses was observed.,

Serial peelings

Some studies have described the effect of serial peelings with glycolic acid, trichloroacetic acid (TCA), and salicylic acid in animal models previously exposed to UV radiation; they observed reduction of mutated p53 and expression of COX-2 mRNA, demonstrating a possible role in tumor prevention., , In humans, there are few studies with a high level of evidence on the subject. A split-face study including 15 patients with facial actinic keratoses a single session of Jessner’s peel plus TCA 35% achieved similar effectiveness to the use of 5-FU twice daily for three weeks. There was a reduction of 75% in the total number of lesions in both groups, in addition to a similar reduction between treatments in keratinocytes atypia, parakeratosis, hyperkeratosis, and inflammation in the histopathological analysis.

More recently, the association of glycolic acid or Jessner’s peel with 5-FU 5% at fortnightly intervals demonstrated effectiveness for treatment of field cancerization; 31 patients were submitted to the sessions until complete lesion remission or until completing ten sessions. The treatment was effective and showed good tolerability; moreover, only five patients presented relapses after 36 months of follow-up.

Oral retinoids

Oral retinoids, synthetic derivatives of vitamin A, are used for chemoprevention of NMSC in high-risk patients for both immunocompetent and immunosuppressed patients, including patients with genodermatoses, such as xeroderma pigmentosum., The main medications described in the studies are acitretin, etretinate, and isotretinoin; among them, acitretin has the greatest degree of evidence regarding its protective effect. Several mechanisms of action are proposed to explain the chemopreventive effect of retinoids, including immunomodulation, apoptosis, promotion of cell differentiation, and inhibition of keratinization and cell proliferation. The first randomized clinical trial evaluating the use of 5 mg etretinate three times a week in 100 patients with actinic keratoses for a period of two months observed complete or partial remission of actinic keratoses in 84% of the treated patients (37 of 44 patients) vs. 5% (2 of 42 patients) in the placebo group.

Another clinical trial with acitretin 30 mg daily for six months in 44 transplant recipients patients observed a 13.4% reduction in actinic keratoses in the treated group vs. an increase of 28.2% in the number of actinic keratoses in the placebo group. In addition, there was a reduction in the appearance of new SCCs in the acitretin group: only two of the 19 patients in the intervention group (11%) developed SCCs vs. nine of the 19 patients of the placebo group (47%) (the relative risk reduction of developing SCCs was of 78% for patients taking acitretin)., Smit et al. evaluated the use of acitretin 0.4 mg/kg/day for three months in 33 renal transplant recipients and performed the histological and immunohistochemical analysis; modifications observed in actinic keratoses were the reduction of an epidermal thickness (p < 0.002) and normalization of the K10 keratinization pattern (p < 0.02). However, there was no change in cell proliferation, which could explain the early recurrence of actinic keratoses after acitretin discontinuation. Data on the optimal dose and duration of treatment are not defined in the literature.

Oral nicotinamide

Nicotinamide, the amide form of vitamin B3, is a cofactor for ATP production that prevents ATP depletion and glycolytic blockade induced by UV radiation, and thus assists in DNA repair. In addition, nicotinamide reduces UV-induced immunosuppression without altering basal immunity. Studies for the prevention of actinic keratoses are sparse, and its use for this purpose is still debated.

The use of nicotinamide as a chemoprotective agent to reduce the appearance of new lesions of NMSC and actinic keratoses in high-risk patients, a 1 g daily dose of the medication divided into two doses, was considered effective. After 12 months of follow-up, the rates of onset of new lesions in the patients receiving nicotinamide were 23% lower compared to the placebo group (p = 0.02), with reduction of both new basal cell carcinomas (20% reduction) and SCCs (30% reduction), as well as actinic keratoses (13%). The protective effect was maintained only during the use of the medication, which presented a good safety profile. However, subsequent studies are needed to confirm the reproducibility of the beneficial effects found, as well as the appropriate treatment duration.

Photoprotection

All patients with actinic keratosis should be advised regarding physical photoprotection and the use of sunscreens as an adjuvant to the treatment, and to prevent the onset of new lesions, regardless of the type of treatment proposed.,  Regular use of sunscreen with a sun protection factor (SPF) over 15 reduces the development of new actinic keratoses in immunocompetent patients, ranging from a 50% reduction in the number of new lesions in one year (study using SPF 29) and 37% in two years (study using SPF 16) (p < 0.05)., In addition, patients who benefit the most from sunscreen use to slow the development of new actinic keratoses include young patients who have not had previous NMSC and those who tan after sunbathing (phototypes ≥III). For immunocompromised patients, a case-control study with 120 immunosuppressed patients followed for 24 months observed that the use of broad-spectrum SPF 50 sunscreen significantly reduced the appearance of new lesions in the intervention group (p < 0.05). Moreover, the effect of daily sunscreen use on spontaneous regression of actinic keratoses is also observed in both immunocompetent and immunosuppressed patients; this regression is higher than that observed in the lesions of patients who do not use sunscreen., , , In addition, the daily use of sunscreen reduces the incidence of new SCCs (p < 0.01).,

Prevention of actinic keratoses is important because the condition can precede cancer or be an early form of skin cancer. Sun safety is necessary to help prevent the development and recurrence of actinic keratosis patches and spots.

Take these steps to protect your skin from the sun:

  • Limit your time in the sun – Especially avoid time in the sun between 10 a.m. and 2 p.m. And avoid staying in the sun so long that you get sunburn or a suntan. Both result in skin damage that can increase your risk of developing actinic keratoses and skin cancer. Sun exposure accumulated over time may also cause actinic keratoses.
  • Use sunscreen. Daily use of sunscreen reduces the development of actinic keratoses. Before spending time outdoors, apply a broad-spectrum sunscreen with a sun protection factor (SPF) of at least 30. The American Academy of Dermatology recommends using a broad-spectrum, water-resistant sunscreen with an SPF of at least 30. Use sunscreen on all exposed skin, and use a lip balm with sunscreen on your lips. Apply sunscreen 15 minutes before sun exposure and reapply it every two hours — or more often if you’re swimming or perspiring.
  • Cover up – For extra protection from the sun, wear tightly woven clothing that covers your arms and legs. Also wear a broad-brimmed hat, which provides more protection than does a baseball cap or golf visor. You might also consider wearing clothing or outdoor gear specially designed to provide sun protection.
  • Avoid tanning beds – The UV exposure from a tanning bed can cause just as much skin damage as a tan acquired from the sun.
  • Check your skin regularly and report changes to your doctor – Examine your skin regularly, looking for the development of new skin growths or changes in existing moles, freckles, bumps, and birthmarks. With the help of mirrors, check your face, neck, ears, and scalp. Examine the tops and undersides of your arms and hands.

References

Actinic Keratoses – Causes, Symptoms, Treatment

Actinic Keratoses (AKs), also referred to as senile keratoses or solar keratoses, are benign intra-epithelial neoplasms and represent one of the most common skin disorders evaluated by dermatologists. Often associated with chronic sun exposure, individuals with AKs may present with irregular, red, scaly papules or plaques on sun-exposed regions of the body. If left untreated, AKs have the potential to evolve into invasive squamous cell carcinoma, which underscores the importance of early detection and development of a treatment plan. There are a variety of management options that are available for AKs, which will be covered in this review.

Another Name

  • Cheilitis,
  • actinic (Actinic cheilitis, solar cheilitis, actinic cheilosis, cheilitis actinic, cheilosis actinic, actinic keratosis of the lip, solar keratosis of the lip, cheilitis exfoliativa).

Pathophysiology

The pathophysiology of actinic keratoses development is complex. Excessive and cumulative UV radiation exposure from the sun can induce a number of pathologic changes to the epidermal keratinocyte through the disruption of regulatory pathways involved in cell growth and differentiation. The resulting inflammation and immunosuppression lead to the intraepidermal proliferation of dysplastic keratinocytes, which give rise to AKs.

Causes of Actinic Keratoses

Actinic keratoses typically develop from the damaging effects of ultraviolet (UV) radiation to the skin accumulated over a lifetime of sun exposure. Actinic keratoses are predominantly located on chronically sun-exposed areas of the body such as the face, scalp (bald or thinning), back of the arms, and dorsal aspect of the hands, especially in older people who have accumulated decades of sun exposure. There are numerous independent risk factors associated with the development of AKs, including:

  • Increased Age – AKs increasingly affect the older population due to the high cumulative lifetime exposure to the sun and inadequate sun protection.
  • Male Gender – AK prevalence is higher in men compared to women.
  • Fair-skinned individuals (Fitzpatrick Skin Phototypes I and II) – Pale or light-skinned individuals have less melanin pigment in the skin and tend to burn easily with sun exposure. Other characteristics of these skin phototypes may include red or blonde hair and blue or light-colored eyes.
  • Geographic Location – Countries located closer to the equator demonstrate higher rates of AKs. For example, prevalence rates of AKs in Australia are close to 60% due to its proximity to the equator (in addition to its sizable White population). In contrast, the prevalence of AKs in a non-equatorial location, such as the United States, is around 20%.
  • Immunosuppression – Individuals with a compromised immune system have an increased susceptibility to develop AKs, such as observed with chemotherapy, acquired immune deficiency syndrome, immunosuppressive medications (transplant medications), and leukemia.
  • History of Actinic Keratosis and/or Previous Skin Malignancy – This important component of the history may indicate genetic factors associated with increased susceptibility to UV radiation as well as the chronicity of UV radiation exposure to which the individual has been exposed.
  • Excessive and Chronic Sun Exposure – People with greater cumulative lifetime exposure to UV radiation from the sun are more prone to developing AKs. At-risk individuals include those with outdoor occupations (e.g., construction, farming) and outdoor activities (e.g., tennis, golf, baseball players).

Symptoms of Actinic Keratoses

The signs and symptoms of an actinic keratosis include:

  • A rough, dry or scaly patch of skin, usually less than 1 inch (2.5 centimeters) in diameter
  • Flat to slightly raised patch or bump on the top layer of skin
  • In some cases, a hard, wartlike surface
  • Color as varied as pink, red or brown
  • Itching or burning in the affected area

Diagnosis of Actinic Keratoses

The primary histopathologic feature of actinic keratoses is atypical keratinocytes in sun-damaged skin that is limited to the lower third of the epidermis.

History and Physical

Important elements of the patient history include

  • Presenting symptoms (pruritus, pain, bleeding with minor trauma) of the lesion(s), a thorough review of medical problems and medications, previous skin cancer treatments/surgery, and a thorough assessment of all risk factors as outlined above, including duration/history of sun exposure, history of sunburn, use of sunscreen, sun protection habits, and occupation.
  • The physical exam involves a detailed full-body skin exam with particular attention to the number, size, distribution, and description of any suspicious skin lesions or skin pathology, especially in the sun-exposed areas of the body (head, face scalp, neck, dorsal forearms, hands). The presence of any ulceration and bleeding should be noted. AKs may appear as scaly, erythematous macules, papules, plaques, or cutaneous horns. Surrounding skin changes may indicate solar damage. AKs often are better appreciated by their rough texture on palpation as they may demonstrate differing degrees of hyperkeratosis.

Evaluation

  • Evaluation of actinic keratoses is primarily by clinical observation during the physical examination. In some cases, useful diagnostic adjuncts to the clinical exam may include dermoscopy or biopsy. On dermoscopy, non-pigmented facial AKs are characterized by a strawberry pattern and include an erythematous vessel pseudo network, prominent follicular openings, and a surrounding white halo.
  • A shave or punch biopsy may be recommended in cases of diagnostic uncertainty, failure to respond to treatment, or in situations where one wants to determine whether an AK has progressed to squamous cell carcinoma.

Treatment

Dermatologists often recommend treatment, long-term follow-up, and preventive strategies to reduce symptomatic actinic keratoses, as well as development and progression to squamous cell carcinoma. The average risk for malignant transformation is 8% in immunocompetent patients, with a range from 0.025% to 16%.

Although there are a variety of options available for the treatment of AKs, the treatment mantra is the same: “no pain, no gain.” Lesion-directed therapies (e.g., cryotherapy, curettage, surgery) target individual AKs, whereas field-directed therapies (e.g., topical medications, light-based therapies, laser resurfacing) have the advantage of treating multiple, widespread, and subclinical AKs that may be within a field of chronic sun damage.

Treatment strategies should be individualized, taking into account several factors: AK’s characteristics and symptoms, patient desires/expectations, treatment availability, patient’s ability to comply with treatment regimens, tolerability of treatment side effects, and cost. Urgency is indicated when lesions are numerous, bleeding, painful, and/or rapidly growing in size. The timeline of expected side effects of blistering, erosion, crusting, burning, discomfort, pain, pruritus, erythema, and edema must be reviewed, as well as how to care for the skin as it heals, regenerates, and recovers from the treatment.

No treatment is without risks. All AK treatments may result in the following potential adverse effects: pain, inflammation, healing issues, pigment changes, and scarring. Recurrence and need for more than one treatment are not uncommon. Healing may take days to weeks, depending on location and number of lesions treated. AKs that fail to respond to aggressive treatment should prompt consideration of treatment noncompliance, misdiagnosis, and possible malignant transformation to squamous cell carcinoma.

AKs are a cutaneous manifestation of repeated sun exposure. Patients diagnosed with AKs should undergo skin cancer screening. Photoprotection strategies and self-skin cancer surveillance should be reviewed with these individuals. Vitamin B3 dosed at 500 mg twice a day has been shown to reduce the number of AKs after several months of use.

Lesion-Directed Treatments: Target individual AKs

  • Cryotherapy – Cryotherapy is a commonly used lesion-directed treatment modality for AKs. It involves the freezing of skin lesions through the topical application of liquid nitrogen via spray or cotton tip applicator. With excellent response rates, it is a viable treatment option for patients with only a few AKs or isolated lesions. Healing will depend on the duration of liquid nitrogen application and the number of freeze-thaw cycles.
  • Curettage or Shave – Lesion removal with a curette or blade can be used for hyperkeratotic AKs that may be unresponsive to alternative treatments. Curettage or shave allows specimen collection for histopathologic evaluation. Electrodessication can be added following curettage to assist with hemostasis.
  • Chemical peel – This is a medical-grade chemical peel used to destroy the top layers of skin. You cannot get this type of chemical peel at a salon or from a kit sold for home use. After a medical-grade chemical peel, the treated skin will be red, swollen, and sore. As the area heals, you will see new healthy skin.
  • Curettage – If you have an extremely thick AK, this may the best treatment. During this procedure, your dermatologist first scrapes the AK from your skin, using a technique called curettage. Your dermatologist may follow this with an electrodesiccation, which heats the treated area to destroy any remaining AK cells.
  • Laser resurfacing – This may be a treatment option for actinic cheilitis, a precancerous growth on the lip. It works by removing the surface layer of the skin. After treatment, the skin will feel raw and sore. When it heals in 1 or 2 weeks, you see new, healthier skin.
  • Chemotherapy. A topical cancer medicinal cream called fluorouracil is applied to the skin lesion or the entire sun-damaged area. It takes around 4 to 6 weeks to work. Usually, the skin turns red and blisters before new skin appears.
  • Photodynamic therapy –  A chemical is applied to the skin. Then the skin is exposed to a light that activates the chemical to destroy the abnormal skin cells. There can be burning, stinging, and changes in pigmentation of the skin.
  • Chemical peel – A chemical solution is applied to the skin to cause blistering and peeling away of the actinic keratoses. Temporary redness and swelling will likely occur.
  • Dermabrasion – This uses a handheld device to “sand” the skin and improve its appearance. It can be used to treat large lesions that are often too big to treat with topical treatments. It leaves the skin red and raw and can be a painful procedure. A topical numbing ointment, nerve blocks, or other pain medications are often used.
  • Immunomodulator therapy – Imiquimod cream, ingenol gel, or diclofenac gel works much like fluorouracil to selectively rid the skin of abnormal cells. There may be redness, itching, swelling, crusting, and peeling

At-home treatment for actinic keratosis

If you have many AKs or AKs that you can feel but not see, your dermatologist may recommend at-home treatment.

  • When you treat at home, you apply medication to your skin as directed.
  • The advantage of using a medication to treat your AKs is that the medication can treat many AKs, including the ones you cannot see yet. Using this approach can reduce your risk of developing new AKs and possibly skin cancer.
  • The downside of applying medication to your skin is that some patients say it’s difficult to follow the treatment plan. To be effective, you need to apply the medication as often as your dermatologist recommends. Even when the medication causes a skin reaction, which indicates that it’s working, you’ll need to keep applying the medication.
  • The medications that dermatologists prescribe include the following, which have all been approved by the US. Food and Drug Administration (FDA) to treat AKs:
  • 5-fluorouracil (5-FU) cream – You apply this once or twice a day for 2 to 4 weeks. It’s often a treatment option for the chest, arms, or back, but usually not the face due to the skin reaction it causes. This is not a treatment option for a woman who is pregnant. 5-FU can harm an unborn baby.
  • Diclofenac sodium gel – This medication tends to cause less of a skin reaction than 5-FU, but it can still be very effective. You will need to apply it twice a day for 2 to 3 months. While using this medication, you must protect your treated skin from the sun. Your dermatologist can tell you the best way to protect your skin.
  • Imiquimod cream – This can be a good option for the face because you can apply it once (or twice) a week, so you don’t get lots of redness and crusting. You may need to apply it for 12 to 16 weeks. If 12 to 16 weeks is too long, you may be able to use the medication a bit differently. You’d apply imiquimod every night for 2 weeks. For the next 2 weeks, you’d give your skin a break. Then you’d apply it again, using it every night for 2 weeks.
  • Ingenol mebutate gel – This requires the shortest treatment time. To treat your face or scalp, you’d apply it for 3 days. On other parts of your body, you’d apply it for 2 days. While you apply this medication for the least amount of time, your skin will still react. For 1 or 2 weeks, you may have a reaction on your face or scalp, such as redness, swelling, crusting, or scaly skin. Reactions can last for up to 4 weeks on the other parts of your body.

Surgery

Surgical excision can be considered when the diagnosis is unclear or if there is a high suspicion of squamous cell carcinoma. Surgical excision will yield tissue for histopathologic diagnosis and help guide further treatment.

  • Surgical removal and biopsy The lesion may be removed and examined if there is a possibility it has become cancerous.
  • Field-Directed Treatments – Treat multiple, widespread, and subclinical AKs that may be within a field of chronic sun damage
  • Dermabrasion – In dermabrasion, a motorized handheld device with attached abrasive material is used to remove the superficial skin layers in areas of actinic damage.
  • Laser – Ablative resurfacing lasers (e.g., CO2 and erbium-YAG lasers) can be used to treat AKs by ablating the epidermis and superficial dermis.
  • Chemical Peels – Chemical peels have been used to treat patients with multiple or widespread facial AKs. A chemical peel involves the topical application of a caustic agent, such as trichloroacetic acid (TCA), to remove the outer skin layers to variable depths. The depth of the peel depends on the agent used, its concentration, and the duration of application. Peels for AKs are approximately 75% effective.
  • Photodynamic Therapy (PDT) – PDT involves the topical application of a photosensitizer to the treatment area and exposure to a light source of a specified wavelength, depending on the depth of skin penetration desired. The generation of reactive oxygen species leads to the destruction of atypical keratinocytes. PDT therapy is an office-based treatment. Disadvantages of conventional PDT include patient complaints of pain, extended time spent in the office during treatment sessions as well as frequent office visits for treatment. These drawbacks have prompted the development of alternative uses of PDT, including daylight photodynamic therapy, where natural daylight is used to activate the photosensitizer in place of an artificial light source. Daylight PDT reportedly has a similar lesion response rate compared to conventional PDT with the advantages of less patient discomfort and added convenience of treatment outside of the office setting.
  • Topical Medications – There are several FDA-approved topical medications for the treatment of AKs. Because the patient at home can apply these medications, patient education is imperative to obtain a favorable outcome and compliance with recommended treatment. The timeline of expected side effects of blistering, erosion, crusting, burning, discomfort, pain, pruritus, erythema, and edema must be reviewed, as well as how to care for the skin at home as it heals and recovers from the field treatment. Numerous treatment regimens have been reported for each of the drugs.
  • 5-Fluorouracil (5-FU) – 5-FU is an FDA-approved topical medication and applied one to two times per day for several weeks. 5-FU, a pyrimidine analog, acts by blocking DNA synthesis and disrupting cell division, providing some of the most effective treatment for AKs.
  • Imiquimod (IMQ) – IMQ is an FDA-approved treatment for AKs. IMQ functions to augment the patient’s immune response at the site of medicine application. It is typically indicated in limited areas of the face and scalp over several weeks.
  • Diclofenac Sodium (DFS) – DFS gel is a topical, non-steroidal, anti-inflammatory FDA-approved drug for AK treatment. The treatment regimen involves application two times per day over a course of two to three months. DFS treatment appears to be better tolerated by patients compared to 5-FU because of milder adverse skin effects.
  • Ingenol mebutate (IM) – IM is obtained from the Euphorbia peplus plant and is FDA-approved for the treatment of AKs. The mechanism of action involves rapid induction of keratinocyte cell death within a few hours and an inflammatory response over the ensuing days, which is immunostimulatory. An advantage of IM treatment is that the duration of therapy is only a couple of days, thus significantly shorter than the other topical drug treatments.

Ablative-surgical treatments

Curettage

  • The use of curettage under local anesthesia for treatment of actinic keratoses can be performed in isolation or in association with electrodesiccation, which appears to increase the resolution of potential remaining dysplastic cells and also to achieve hemostasis. An alternative to electrodesiccation is cryotherapy. As a monotherapy, a curettage is especially indicated for patients with few lesions, especially hyperkeratotic actinic keratoses. The method is frequently used in the setting of patients with large clinical variability of keratoses as a complementary therapy for lesions resistant to field cancerization therapy, in addition to allowing the collection of material for histopathological analysis.
  • Disadvantages regarding the method include the need for local anesthesia, the healing time, which can be prolonged when lesions are treated especially in the lower limbs, and the risk of dyspigmentation symptoms in the treated area., Although curettage is widely performed in daily practice, the lack of randomized clinical trials evaluating the subject results in a low degree of the recommendation of the procedure for actinic keratoses treatment.

CO2 laser

  • Lasers induce coagulative necrosis, ablation, and hyperthermia, which lead to lesional destruction. A single session of non-fractional CO2 laser could be used to remove superficial lesions on the epidermis, such as actinic keratoses. The 10,600 nm CO2 non-fractional laser has a wavelength absorbed by water, resulting in non-specific tissue destruction. Therefore, the non-fractional CO2 laser can be used for field cancerization treatment or for localized lesion destruction.
  • For localized lesions, complete lesion clearance results in the first months are similar to those obtained with cryotherapy (72.8% in the laser group vs. 78% for cryotherapy); however, in long-term follow-up, lesions treated with CO2 laser present lower sustained response rates: only 37% of the patients treated with laser remain without lesions vs. 66.8% of those treated with cryotherapy. Furthermore, because the technique is operator-dependent, different levels of expertise with the technique may influence the results. In addition, there is a risk of secondary infection, esthetical scars, and dyschromia.
  • Because of the increased risk of infection in immunosuppressed patients, the CO2 laser is not recommended for the treatment of field cancerization and should be used only for localized lesions in these patients. Although the use of CO2 laser can be considered as an option for actinic keratoses treatment, the degree of recommendation for its use in immunocompetent patients is weak.

Prevention

Topical retinoids

One of the first studies to report the benefits of topical retinoids for patients with actinic keratoses dates back to 1970, a case series of 60 patients that reported benefits of tretinoin use at 0.1–0.3%, for a reduction in actinic keratoses scores of about 50%. Subsequent studies have shown that tretinoin at a lower concentration (0.05%) was not as effective, with a maximum reduction in the number of actinic keratoses of 45%., However, despite these initial positive results, more recent studies evaluating the use of topical retinoids in a larger sample (>1000 individuals) have not been able to demonstrate their efficacy in reducing the occurrence of SCC and basal cell carcinoma (BCC) in patients at risk; besides, no benefit in reducing the number of actinic keratoses was observed.,

Serial peelings

Some studies have described the effect of serial peelings with glycolic acid, trichloroacetic acid (TCA), and salicylic acid in animal models previously exposed to UV radiation; they observed reduction of mutated p53 and expression of COX-2 mRNA, demonstrating a possible role in tumor prevention., , In humans, there are few studies with a high level of evidence on the subject. A split-face study including 15 patients with facial actinic keratoses a single session of Jessner’s peel plus TCA 35% achieved similar effectiveness to the use of 5-FU twice daily for three weeks. There was a reduction of 75% in the total number of lesions in both groups, in addition to a similar reduction between treatments in keratinocytes atypia, parakeratosis, hyperkeratosis, and inflammation in the histopathological analysis.

More recently, the association of glycolic acid or Jessner’s peel with 5-FU 5% at fortnightly intervals demonstrated effectiveness for treatment of field cancerization; 31 patients were submitted to the sessions until complete lesion remission or until completing ten sessions. The treatment was effective and showed good tolerability; moreover, only five patients presented relapses after 36 months of follow-up.

Oral retinoids

Oral retinoids, synthetic derivatives of vitamin A, are used for chemoprevention of NMSC in high-risk patients for both immunocompetent and immunosuppressed patients, including patients with genodermatoses, such as xeroderma pigmentosum., The main medications described in the studies are acitretin, etretinate, and isotretinoin; among them, acitretin has the greatest degree of evidence regarding its protective effect. Several mechanisms of action are proposed to explain the chemopreventive effect of retinoids, including immunomodulation, apoptosis, promotion of cell differentiation, and inhibition of keratinization and cell proliferation. The first randomized clinical trial evaluating the use of 5 mg etretinate three times a week in 100 patients with actinic keratoses for a period of two months observed complete or partial remission of actinic keratoses in 84% of the treated patients (37 of 44 patients) vs. 5% (2 of 42 patients) in the placebo group.

Another clinical trial with acitretin 30 mg daily for six months in 44 transplant recipients patients observed a 13.4% reduction in actinic keratoses in the treated group vs. an increase of 28.2% in the number of actinic keratoses in the placebo group. In addition, there was a reduction in the appearance of new SCCs in the acitretin group: only two of the 19 patients in the intervention group (11%) developed SCCs vs. nine of the 19 patients of the placebo group (47%) (the relative risk reduction of developing SCCs was of 78% for patients taking acitretin)., Smit et al. evaluated the use of acitretin 0.4 mg/kg/day for three months in 33 renal transplant recipients and performed the histological and immunohistochemical analysis; modifications observed in actinic keratoses were the reduction of an epidermal thickness (p < 0.002) and normalization of the K10 keratinization pattern (p < 0.02). However, there was no change in cell proliferation, which could explain the early recurrence of actinic keratoses after acitretin discontinuation. Data on the optimal dose and duration of treatment are not defined in the literature.

Oral nicotinamide

Nicotinamide, the amide form of vitamin B3, is a cofactor for ATP production that prevents ATP depletion and glycolytic blockade induced by UV radiation, and thus assists in DNA repair. In addition, nicotinamide reduces UV-induced immunosuppression without altering basal immunity. Studies for the prevention of actinic keratoses are sparse, and its use for this purpose is still debated.

The use of nicotinamide as a chemoprotective agent to reduce the appearance of new lesions of NMSC and actinic keratoses in high-risk patients, a 1 g daily dose of the medication divided into two doses, was considered effective. After 12 months of follow-up, the rates of onset of new lesions in the patients receiving nicotinamide were 23% lower compared to the placebo group (p = 0.02), with reduction of both new basal cell carcinomas (20% reduction) and SCCs (30% reduction), as well as actinic keratoses (13%). The protective effect was maintained only during the use of the medication, which presented a good safety profile. However, subsequent studies are needed to confirm the reproducibility of the beneficial effects found, as well as the appropriate treatment duration.

Photoprotection

All patients with actinic keratosis should be advised regarding physical photoprotection and the use of sunscreens as an adjuvant to the treatment, and to prevent the onset of new lesions, regardless of the type of treatment proposed.,  Regular use of sunscreen with a sun protection factor (SPF) over 15 reduces the development of new actinic keratoses in immunocompetent patients, ranging from a 50% reduction in the number of new lesions in one year (study using SPF 29) and 37% in two years (study using SPF 16) (p < 0.05)., In addition, patients who benefit the most from sunscreen use to slow the development of new actinic keratoses include young patients who have not had previous NMSC and those who tan after sunbathing (phototypes ≥III). For immunocompromised patients, a case-control study with 120 immunosuppressed patients followed for 24 months observed that the use of broad-spectrum SPF 50 sunscreen significantly reduced the appearance of new lesions in the intervention group (p < 0.05). Moreover, the effect of daily sunscreen use on spontaneous regression of actinic keratoses is also observed in both immunocompetent and immunosuppressed patients; this regression is higher than that observed in the lesions of patients who do not use sunscreen., , ,  In addition, daily use of sunscreen reduces the incidence of new SCCs (p < 0.01).,

Prevention of actinic keratoses is important because the condition can precede cancer or be an early form of skin cancer. Sun safety is necessary to help prevent development and recurrence of actinic keratosis patches and spots.

Take these steps to protect your skin from the sun:

  • Limit your time in the sun – Especially avoid time in the sun between 10 a.m. and 2 p.m. And avoid staying in the sun so long that you get sunburn or a suntan. Both result in skin damage that can increase your risk of developing actinic keratoses and skin cancer. Sun exposure accumulated over time may also cause actinic keratoses.
  • Use sunscreen. Daily use of sunscreen reduces the development of actinic keratoses. Before spending time outdoors, apply a broad-spectrum sunscreen with a sun protection factor (SPF) of at least 30. The American Academy of Dermatology recommends using a broad-spectrum, water-resistant sunscreen with an SPF of at least 30. Use sunscreen on all exposed skin, and use lip balm with sunscreen on your lips. Apply sunscreen 15 minutes before sun exposure and reapply it every two hours — or more often if you’re swimming or perspiring.
  • Cover up – For extra protection from the sun, wear tightly woven clothing that covers your arms and legs. Also wear a broad-brimmed hat, which provides more protection than does a baseball cap or golf visor. You might also consider wearing clothing or outdoor gear specially designed to provide sun protection.
  • Avoid tanning beds – The UV exposure from a tanning bed can cause just as much skin damage as a tan acquired from the sun.
  • Check your skin regularly and report changes to your doctor – Examine your skin regularly, looking for the development of new skin growths or changes in existing moles, freckles, bumps and birthmarks. With the help of mirrors, check your face, neck, ears and scalp. Examine the tops and undersides of your arms and hands.

References

Farmer’s Lip – Causes, Symptoms, Treatment

Farmer’s Lip/Actinic cheilitis is cheilitis (lip inflammation) caused by long term sunlight exposure. Essentially it is a burn and a variant of actinic keratosis which occurs on the lip.[rx] It is a premalignant condition,[x] as it can develop into squamous cell carcinoma (a type of mouth cancer).

“Sailor’s Lip,” or actinic cheilitis (AC), is a precursor of squamous cell carcinoma (SCC) found on the lips. Similar to actinic keratosis, actinic cheilitis is a premalignant lesion caused by chronic sun exposure. It is most common on the lower lip along the vermillion border. Given SCC on the lips is considered a high-risk form of skin cancer with an 11% chance of metastasis compared to 1% for other body locations, it is essential to recognize and appropriately manage these potentially malignant precursory lesions.

Actinic cheilitis, also known as solar cheilosis, farmer’s lip, or sailor’s lip, is a reaction to long-term sun exposure on the lips, primarily the lower lip. The lip is especially susceptible to UV radiation because it has a thinner epithelium and less pigment. Some believe actinic cheilitis represents a type of actinic keratosis and is therefore premalignant. Others believe it is a form of in-situ squamous cell carcinoma. Regardless, the literature is in agreement that its presence indicates an increased risk for invasive squamous cell carcinoma.

Pathophysiology

Those with fair skin have less melanin and innately less protection against UV rays. The physical properties of the lips, such as their shape and being a transition area from oral mucosa to skin with thinner epithelium, less sebaceous glands, and less melanin, contribute to less protection and increased exposure to UV radiation. Chronic exposure to UV light damages tumor suppressor gene p53 resulting in uncontrolled replication of defective cells, which is a common gene mutation found with increasing frequency as actinic cheilitis and actinic keratoses undergo malignant transformation to SCC. Although actinic cheilitis can affect both the upper and lower oral cutaneous mucosa, more light from the sun hits the lower lip, making this area especially prone to sun damage and an increased number of skin cancers.

Causes of Farmer’s Lip

Actinic cheilitis results from the sun or UV radiation exposure. Additional risk factors include increased age, especially over 60 years, Fitzpatrick I and II skin types, genetic abnormalities affecting pigmentation such as albinism, working more than 25yrs outdoors, or a history of nonmelanoma skin cancer (NMSC). There has been conflicting evidence as to whether alcohol and smoking independently increase the risk of AC.AC is caused by chronic and excessive exposure to ultraviolet radiation in sunlight.

Risk factors include

  • Outdoor lifestyle – e.g. farmers, sailors, fishermen, windsurfers, mountaineers, golfers, etc.[rx] This has given rise to synonyms for this condition such as “sailor’s lip” and “farmer’s lip”.[rx] The prevalence in agricultural workers in a semi-arid region of Brazil is reported to be 16.7%.[rx]
  • Light skin complexion – the condition typically affects individuals with lighter skin tones,[rx] particularly Caucasians living in tropical regions.[rx] In one report, 96% of persons with AC had phenotype II according to the Fitzpatrick scale.[rx]
  • Age – AC typically affects older individuals, and rarely those under the age of 45.
  • Gender – the condition affects males more commonly than females. Sometimes this ratio is reported as high as 10:1. Additional factors may also play a role, including tobacco use, lip irritation, poor oral hygiene, and ill-fitting dentures.[rx]

Symptoms of Farmer’s Lip

AC almost always affects the lower lip and only rarely the upper lip, probably because the lower lip is more exposed to the sun. In the unusual cases reported where it affects the upper lip, this may be due to upper lip prominence. The commissures (corners of the mouth) are not usually involved.[rx][rx]

  • Affected individuals may experience symptoms such as a dry sensation and cracking of the lips.[rx] It is usually painless and persistent.
  • The appearance is variable. White lesions indicate hyperkeratosis. Red, erosive or ulcerative lesions indicate atrophy, loss of epithelium, and inflammation. Early, acute lesions may be erythematous (red) and edematous (swollen). With months and years of sun exposure, the lesion becomes chronic and may be grey-white in color and appear dry, scaly, and wrinkled.[rx]
  • There is thickening whitish discoloration of the lip at the border of the lip and skin. There is also a loss of the usually sharp border between the red of the lip and the normal skin, known as the vermillion border. The lip may become scaly and indurated as AC progresses.
  • When palpated, the lip may have a texture similar to rubbing the gloved finger along with sandpaper.[rx]
  • AC may occur with skin lesions of actinic keratosis or skin cancer elsewhere, particularly on the head and neck[rx] since these are the most sun-exposed areas. Rarely it may represent a genetic susceptibility to light damage (e.g. xeroderma pigmentosum or actinic prurigo).[rx]

Diagnosis of Farmer’s Lip

Biopsy w/ H&E is recommended for persistent suspicious lip lesions to rule out invasive skin cancer. Basic histopathology for actinic cheilitis would be:

  • Hyperkeratosis: thickening of stratum corneum
  • Solar elastosis:  loss of eosin staining, accumulation of irregular thick elastic fibers and tangled fibrillin
  • Epithelial dysplasia (mild-moderate): disordered maturation of epidermal cells, loss of rete ridges, variable cytological atypia
  • Perivascular inflammation: inflammatory cells around the blood vessels
  • Severe dysplasia: increase in dyskeratosis, keratin pearls, drop-shaped projections, and nuclei related changes such as mitoses and pleomorphism indicate the progression of dysplasia and increased malignant transformation.

History and Physical

  • Persistent white plaque with “sandpapery” feel on the lips
  • Most commonly lower lip
  • Blurring of the vermillion border between the cutaneous and mucosal lip
  • Usually asymptomatic/painless, but may have burning, numbness, pain
  • Eventually, plaque may become indurated, scaly and ulcerate as lesion progresses
  • Outdoor laborers: sailors, farmers, construction workers, lifeguards
  • Fitzpatrick I-II fair-skinned individuals

Evaluation

Actinic cheilitis is a diagnosis made from clinical and histopathology evaluation. It is essential to distinguish between cheilitis (benign inflammation),  premalignant actinic cheilitis, and squamous cell carcinoma. Skin biopsy is the golden standard regarding the evaluation of a persistent suspicious lesion on the lip. Many lesions initially thought to be premalignant actinic cheilitis on exam were found to be SCC upon histological evaluation, which indicates providers are not able to entirely make the diagnosis clinically, and biopsy is helpful when evaluating these lesions. While not required to make a diagnosis, one article suggests evaluating patients with electron microscopy helps to assess further the ultrastructural changes found in AC lesions, their potential for malignant transformation, and ensure they are diagnosed and managed correctly.

  • Physical exam – persistent white/erythematous thickening sandpapery skin on the lower lip
  • Labwork – for lesions that are new, symmetric, in young patients, found in patient’s with darker skin types, or individuals without a history of chronic sun exposure where skin cancer is less likely, consider first ruling out reversible causes such as those with a vitamin deficiency/infectious/contact/irritant etiology (Chart 1)
  • Skin biopsy – skin biopsy is recommended for persistent lesions
  • Electron Microscopy – hyperkeratosis, mild acanthosis, Perivascular lymphocytic infiltrate around glandular ducts

Treatment of Farmer’s Lip

MEDICAL OPTIONS

  • Topical treatments (ie, chemotherapeutic versus immunotherapy)
  • Topical 5-Fluourouracil
  • Imiquimod
  • Trichloroacetic Acid Peel 50%

SURGICAL

  • Localized shave removal
  • Vermilionectomy

PHYSICAL MODALITIES

  • Cryotherapy
  • Electrosurgery
  • CO2 laser resurfacing
  • Er:YAG laser resurfacing
  • Photodynamic therapy (PDT)
  • Dermabrasion

Treatment of actinic cheilitis should depend on the size, location, and severity of the lesion, along with the patient’s other comorbidities. The goal of therapy is to reduce the risk of malignant transformation from AC to SCC while maintaining functionality and cosmesis of the lips. A variety of therapies targeted at removing the dysplastic epithelium have been used to manage AC, including both surgical and medical options.

Surgical/destructive options for treatment include excisional vermilionectomy, cryotherapy, electrocautery, and pulse-dye or CO2 laser. However, these procedures are invasive, and patients may experience adverse effects such as pain, delayed healing, infection, scarring, edema, and paresthesias.

Non-surgical treatments for AC include topical therapies such as 5-fluorouracil, imiquimod, trichloroacetic acid, ingenol mebutate, diclofenac, phototherapy, topical DNA enzyme repair creams, photoprotection, and curettage with methyl aminolevulinate cream/daylight PDT. Many of the topical treatments cause adverse effects such as inflammation, crusting, and pain, which may reduce patient compliance.

A systemic review and meta-analysis of 283 patients showed surgically treated lesions compared to medically managed lesions had a higher remission rate (92.8% vs. 65%) and lower recurrence rates (8.4 vs. 19.2%) than non-surgical treatment. Dermoscopy has been used to aid with diagnosis and monitor treatment management in patients undergoing topical treatment.

It is difficult to directly compare efficacy across the numerous treatment options available for actinic cheilitis since many of the published studies, the severity of actinic cheilitis, and treatment regimens are not consistent or controlled across studies. However, the following options may be an option when deciding management for actinic cheilitis.

Laser treatment: preferred non-surgical intervention (efficacy 93%, low recurrences)

  • CO2 Laser: 10600 nm
  • Erbium Laser: 2940 nm
  • Adverse effects: pain, hypertrophic scarring (managed with corticosteroids)

Vermilionectomy/Surgical excision – preferred treatment for severe/refractory cases (efficacy near 100%, low recurrences).

  • Adverse effects: pain, delayed healing, infection, scarring, edema, paresthesias, may be cosmetically disfiguring compared to other treatment options

Topical Treatments – preferred treatment for patients with large areas of sun damage or those preferring medical intervention

  • Various treatment regimens studied, examples range from applying to affected area once daily for 1 to 4 weeks depending on patient’s tolerability (Efficacy for 5-FU at one week 69%, increased to 91% efficacy at four weeks)
  • Adverse effects: pain, crusting, inflammation, reduced patient compliance
  • Summary of Topical Options and Their Mechanism of Action

    • 5-FU: impairs pyrimidine thymidine synthesis and DNA replication
    • Imiquimod: nucleoside analog and immunostimulator
    • Ingenol mebutate: induces cell death and neutrophil-mediated antibody-dependent immune response to clear tumors
    • Trichloroacetic acid: induces cell necrosis
    • Diclofenac: anti-inflammatory, induces apoptosis by inhibiting COX 1 and COX2

Phototherapy – while actinic cheilitis results from by UV light damaging epithelial DNA, light therapy at an increased intensity level that causes reactive oxygen species to destroy damaged skin cells and was found to be an effective treatment in some cases (efficacy 68%,12% recurrences). Efficacy increases when used in conjunction with other treatment options, including topical treatments.

  • Adverse effects include pain, recurrence

Cryotherapy – liquid nitrogen physically destroys abnormal cells

  • Adverse effects include pain, crusting, scarring, reduced efficacy compared to other treatment options

Electrocautery/Curettage – physical destruction of the abnormal cells

  • Adverse effects include pain, scarring

Photoprotection – reduce the progression

  •  Dependent on patient compliance

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 the treatment of actinic cheilitis with cryosurgery.

Electrosurgery and localized shave removal are also effective options for discrete areas of actinic cheilitis. Both procedures involve the destruction or removal of clinically involved areas of actinic damage. A local anesthetic is required. Shave removal provides a 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 a 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 super pulsed mode has fewer potential side effects than the continuous waveform. The super pulsed mode reduces the potential for collateral damage by concentrating the energy into rapid pulses with adequate cooling between pulses. The ultra pulsed 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 Sharpton 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 the need for frequent soaks and the 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, valacyclovir 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 a 2940-nm wavelength that targets water and also leads to the 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) passes and coagulation (<1J/cm2, with pulse width between 2-35 ms) pass was 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 a visualization of the 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 the 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-fluorouracil and imiquimod) have been successful at treating actinic cheilitis as they offer a non-surgical option for field treatment. Both are potentially effective treatments, but they are limited by the low rate of patient compliance.

5-fluorouracil (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 the 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. The 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 a topical steroid application. Reactions can be severe and intolerable for patients because of the duration of treatment and impact on the 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 the 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 of 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 the 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 a visualization of the dermis with a dull appearance and pinpoints 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 a clinical recurrence and 100% had a histologic recurrence of dysplasia. Reepithelialization can take 1-3 weeks. Potential side effects include mild discomfort, crusting, edema, and herpes labialis reactivation.

References

Solar Cheilosis – Causes, Symptoms, Diagnosis, Treatment

Solar Cheilosis/Actinic cheilitis is cheilitis (lip inflammation) caused by long term sunlight exposure. Essentially it is a burn, and a variant of actinic keratosis which occurs on the lip.[rx] It is a premalignant condition,[x] as it can develop into squamous cell carcinoma (a type of mouth cancer).

“Sailor’s Lip,” or actinic cheilitis (AC), is a precursor of squamous cell carcinoma (SCC) found on the lips. Similar to actinic keratosis, actinic cheilitis is a premalignant lesion caused by chronic sun exposure. It is most common on the lower lip along the vermillion border. Given SCC on the lips is considered a high-risk form of skin cancer with an 11% chance of metastasis compared to 1% for other body locations, it is essential to recognize and appropriately manage these potentially malignant precursory lesions.

Actinic cheilitis, also known as solar cheilosis, farmer’s lip, or sailor’s lip, is a reaction to long-term sun exposure on the lips, primarily the lower lip. The lip is especially susceptible to UV radiation because it has a thinner epithelium and less pigment. Some believe actinic cheilitis represents a type of actinic keratosis and is therefore premalignant. Others believe it is a form of in-situ squamous cell carcinoma. Regardless, the literature is in agreement that its presence indicates an increased risk for invasive squamous cell carcinoma.

Pathophysiology

Those with fair skin have less melanin and innately less protection against UV rays. The physical properties of the lips, such as their shape and being a transition area from oral mucosa to skin with thinner epithelium, less sebaceous glands, and less melanin, contribute to less protection and increased exposure to UV radiation. Chronic exposure to UV light damages tumor suppressor gene p53 resulting in uncontrolled replication of defective cells, which is a common gene mutation found with increasing frequency as actinic cheilitis and actinic keratoses undergo malignant transformation to SCC. Although actinic cheilitis can affect both the upper and lower oral cutaneous mucosa, more light from the sun hits the lower lip, making this area especially prone to sun damage and an increased number of skin cancers.

Causes of Solar Cheilosis

Actinic cheilitis results from the sun or UV radiation exposure. Additional risk factors include increased age, especially over 60 years, Fitzpatrick I and II skin types, genetic abnormalities affecting pigmentation such as albinism, working more than 25yrs outdoors, or a history of nonmelanoma skin cancer (NMSC). There has been conflicting evidence as to whether alcohol and smoking independently increase the risk of AC.AC is caused by chronic and excessive exposure to ultraviolet radiation in sunlight.

Risk factors include

  • Outdoor lifestyle – e.g. farmers, sailors, fishermen, windsurfers, mountaineers, golfers, etc.[rx] This has given rise to synonyms for this condition such as “sailor’s lip” and “farmer’s lip”.[rx] The prevalence in agricultural workers in a semi-arid region of Brazil is reported to be 16.7%.[rx]
  • Light skin complexion – the condition typically affects individuals with lighter skin tones,[rx] particularly Caucasians living in tropical regions.[rx] In one report, 96% of persons with AC had phenotype II according to the Fitzpatrick scale.[rx]
  • Age – AC typically affects older individuals, and rarely those under the age of 45.
  • Gender – the condition affects males more commonly than females. Sometimes this ratio is reported as high as 10:1. Additional factors may also play a role, including tobacco use, lip irritation, poor oral hygiene, and ill-fitting dentures.[rx]

Symptoms of Solar Cheilosis

AC almost always affects the lower lip and only rarely the upper lip, probably because the lower lip is more exposed to the sun. In the unusual cases reported where it affects the upper lip, this may be due to upper lip prominence. The commissures (corners of the mouth) are not usually involved.[rx][rx]

  • Affected individuals may experience symptoms such as a dry sensation and cracking of the lips.[rx] It is usually painless and persistent.
  • The appearance is variable. White lesions indicate hyperkeratosis. Red, erosive or ulcerative lesions indicate atrophy, loss of epithelium, and inflammation. Early, acute lesions may be erythematous (red) and edematous (swollen). With months and years of sun exposure, the lesion becomes chronic and may be grey-white in color and appear dry, scaly, and wrinkled.[rx]
  • There is thickening whitish discoloration of the lip at the border of the lip and skin. There is also a loss of the usually sharp border between the red of the lip and the normal skin, known as the vermillion border. The lip may become scaly and indurated as AC progresses.
  • When palpated, the lip may have a texture similar to rubbing the gloved finger along with sandpaper.[rx]
  • AC may occur with skin lesions of actinic keratosis or skin cancer elsewhere, particularly on the head and neck[rx] since these are the most sun-exposed areas. Rarely it may represent a genetic susceptibility to light damage (e.g. xeroderma pigmentosum or actinic prurigo).[rx]

Diagnosis of Solar Cheilosis

Biopsy w/ H&E is recommended for persistent suspicious lip lesions to rule out invasive skin cancer. Basic histopathology for actinic cheilitis would be:

  • Hyperkeratosis: thickening of stratum corneum
  • Solar elastosis:  loss of eosin staining, accumulation of irregular thick elastic fibers and tangled fibrillin
  • Epithelial dysplasia (mild-moderate): disordered maturation of epidermal cells, loss of rete ridges, variable cytological atypia
  • Perivascular inflammation: inflammatory cells around the blood vessels
  • Severe dysplasia: increase in dyskeratosis, keratin pearls, drop-shaped projections, and nuclei related changes such as mitoses and pleomorphism indicate the progression of dysplasia and increased malignant transformation.

History and Physical

  • Persistent white plaque with “sandpapery” feel on the lips
  • Most commonly lower lip
  • Blurring of the vermillion border between the cutaneous and mucosal lip
  • Usually asymptomatic/painless, but may have burning, numbness, pain
  • Eventually, plaque may become indurated, scaly and ulcerate as lesion progresses
  • Outdoor laborers: sailors, farmers, construction workers, lifeguards
  • Fitzpatrick I-II fair-skinned individuals

Evaluation

Actinic cheilitis is a diagnosis made from clinical and histopathology evaluation. It is essential to distinguish between cheilitis (benign inflammation),  premalignant actinic cheilitis, and squamous cell carcinoma. Skin biopsy is the golden standard regarding the evaluation of a persistent suspicious lesion on the lip. Many lesions initially thought to be premalignant actinic cheilitis on exam were found to be SCC upon histological evaluation, which indicates providers are not able to entirely make the diagnosis clinically, and biopsy is helpful when evaluating these lesions. While not required to make a diagnosis, one article suggests evaluating patients with electron microscopy helps to assess further the ultrastructural changes found in AC lesions, their potential for malignant transformation, and ensure they are diagnosed and managed correctly.

  • Physical exam – persistent white/erythematous thickening sandpapery skin on the lower lip
  • Labwork – for lesions that are new, symmetric, in young patients, found in patient’s with darker skin types, or individuals without a history of chronic sun exposure where skin cancer is less likely, consider first ruling out reversible causes such as those with a vitamin deficiency/infectious/contact/irritant etiology (Chart 1)
  • Skin biopsy – skin biopsy is recommended for persistent lesions
  • Electron Microscopy – hyperkeratosis, mild acanthosis, Perivascular lymphocytic infiltrate around glandular ducts

Treatment of Solar Cheilosis

MEDICAL OPTIONS

  • Topical treatments (ie, chemotherapeutic versus immunotherapy)
  • Topical 5-Fluourouracil
  • Imiquimod
  • Trichloroacetic Acid Peel 50%

SURGICAL

  • Localized shave removal
  • Vermilionectomy

PHYSICAL MODALITIES

  • Cryotherapy
  • Electrosurgery
  • CO2 laser resurfacing
  • Er:YAG laser resurfacing
  • Photodynamic therapy (PDT)
  • Dermabrasion

Treatment of actinic cheilitis should depend on the size, location, and severity of the lesion, along with the patient’s other comorbidities. The goal of therapy is to reduce the risk of malignant transformation from AC to SCC while maintaining functionality and cosmesis of the lips. A variety of therapies targeted at removing the dysplastic epithelium have been used to manage AC, including both surgical and medical options.

Surgical/destructive options for treatment include excisional vermilionectomy, cryotherapy, electrocautery, and pulse-dye or CO2 laser. However, these procedures are invasive, and patients may experience adverse effects such as pain, delayed healing, infection, scarring, edema, and paresthesias.

Non-surgical treatments for AC include topical therapies such as 5-fluorouracil, imiquimod, trichloroacetic acid, ingenol mebutate, diclofenac, phototherapy, topical DNA enzyme repair creams, photoprotection, and curettage with methyl aminolevulinate cream/daylight PDT. Many of the topical treatments cause adverse effects such as inflammation, crusting, and pain, which may reduce patient compliance.

A systemic review and meta-analysis of 283 patients showed surgically treated lesions compared to medically managed lesions had a higher remission rate (92.8% vs. 65%) and lower recurrence rates (8.4 vs. 19.2%) than non-surgical treatment. Dermoscopy has been used to aid with diagnosis and monitor treatment management in patients undergoing topical treatment.

It is difficult to directly compare efficacy across the numerous treatment options available for actinic cheilitis since many of the published studies, the severity of actinic cheilitis, and treatment regimens are not consistent or controlled across studies. However, the following options may be an option when deciding management for actinic cheilitis.

Laser treatment: preferred non-surgical intervention (efficacy 93%, low recurrences)

  • CO2 Laser: 10600 nm
  • Erbium Laser: 2940 nm
  • Adverse effects: pain, hypertrophic scarring (managed with corticosteroids)

Vermilionectomy/Surgical excision – preferred treatment for severe/refractory cases (efficacy near 100%, low recurrences).

  • Adverse effects: pain, delayed healing, infection, scarring, edema, paresthesias, may be cosmetically disfiguring compared to other treatment options

Topical Treatments – preferred treatment for patients with large areas of sun damage or those preferring medical intervention

  • Various treatment regimens studied, examples range from applying to affected area once daily for 1 to 4 weeks depending on patient’s tolerability (Efficacy for 5-FU at one week 69%, increased to 91% efficacy at four weeks)
  • Adverse effects: pain, crusting, inflammation, reduced patient compliance
  • Summary of Topical Options and Their Mechanism of Action

    • 5-FU: impairs pyrimidine thymidine synthesis and DNA replication
    • Imiquimod: nucleoside analog and immunostimulator
    • Ingenol mebutate: induces cell death and neutrophil-mediated antibody-dependent immune response to clear tumors
    • Trichloroacetic acid: induces cell necrosis
    • Diclofenac: anti-inflammatory, induces apoptosis by inhibiting COX 1 and COX2

Phototherapy – while actinic cheilitis results from by UV light damaging epithelial DNA, light therapy at an increased intensity level that causes reactive oxygen species to destroy damaged skin cells and was found to be an effective treatment in some cases (efficacy 68%,12% recurrences). Efficacy increases when used in conjunction with other treatment options, including topical treatments.

  • Adverse effects include pain, recurrence

Cryotherapy – liquid nitrogen physically destroys abnormal cells

  • Adverse effects include pain, crusting, scarring, reduced efficacy compared to other treatment options

Electrocautery/Curettage – physical destruction of the abnormal cells

  • Adverse effects include pain, scarring

Photoprotection – reduce the progression

  •  Dependent on patient compliance

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 the treatment of actinic cheilitis with cryosurgery.

Electrosurgery and localized shave removal are also effective options for discrete areas of actinic cheilitis. Both procedures involve the destruction or removal of clinically involved areas of actinic damage. A local anesthetic is required. Shave removal provides a 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 a 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 super pulsed mode has fewer potential side effects than the continuous waveform. The super pulsed mode reduces the potential for collateral damage by concentrating the energy into rapid pulses with adequate cooling between pulses. The ultra pulsed 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 Sharpton 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 the need for frequent soaks and the 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, valacyclovir 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 a 2940-nm wavelength that targets water and also leads to the 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) passes and coagulation (<1J/cm2, with pulse width between 2-35 ms) pass was 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 a visualization of the 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 the 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-fluorouracil and imiquimod) have been successful at treating actinic cheilitis as they offer a non-surgical option for field treatment. Both are potentially effective treatments, but they are limited by the low rate of patient compliance.

5-fluorouracil (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 the 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. The 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 a topical steroid application. Reactions can be severe and intolerable for patients because of the duration of treatment and impact on the 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 the 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 of 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 the 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 a visualization of the dermis with a dull appearance and pinpoints 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 a clinical recurrence and 100% had a histologic recurrence of dysplasia. Reepithelialization can take 1-3 weeks. Potential side effects include mild discomfort, crusting, edema, and herpes labialis reactivation.

References

Sailor’s Lip – Causes, Symptoms, Diagnosis, Treatment

Sailor’s Lip/Actinic cheilitis is cheilitis (lip inflammation) caused by long term sunlight exposure. Essentially it is a burn, and a variant of actinic keratosis which occurs on the lip.[rx] It is a premalignant condition,[x] as it can develop into squamous cell carcinoma (a type of mouth cancer).

“Sailor’s Lip,” or actinic cheilitis (AC), is a precursor of squamous cell carcinoma (SCC) found on the lips. Similar to actinic keratosis, actinic cheilitis is a premalignant lesion caused by chronic sun exposure. It is most common on the lower lip along the vermillion border. Given SCC on the lips is considered a high-risk form of skin cancer with an 11% chance of metastasis compared to 1% for other body locations, it is essential to recognize and appropriately manage these potentially malignant precursory lesions.

Actinic cheilitis, also known as solar cheilosis, farmer’s lip, or sailor’s lip, is a reaction to long-term sun exposure on the lips, primarily the lower lip. The lip is especially susceptible to UV radiation because it has a thinner epithelium and less pigment. Some believe actinic cheilitis represents a type of actinic keratosis and is therefore premalignant. Others believe it is a form of in-situ squamous cell carcinoma. Regardless, the literature is in agreement that its presence indicates an increased risk for invasive squamous cell carcinoma.

Pathophysiology

Those with fair skin have less melanin and innately less protection against UV rays. The physical properties of the lips, such as their shape and being a transition area from oral mucosa to skin with thinner epithelium, less sebaceous glands, and less melanin, contribute to less protection and increased exposure to UV radiation. Chronic exposure to UV light damages tumor suppressor gene p53 resulting in uncontrolled replication of defective cells, which is a common gene mutation found with increasing frequency as actinic cheilitis and actinic keratoses undergo malignant transformation to SCC. Although actinic cheilitis can affect both the upper and lower oral cutaneous mucosa, more light from the sun hits the lower lip, making this area especially prone to sun damage and an increased number of skin cancers.

Causes of Sailor’s Lip

Actinic cheilitis results from the sun or UV radiation exposure. Additional risk factors include increased age, especially over 60 years, Fitzpatrick I and II skin types, genetic abnormalities affecting pigmentation such as albinism, working more than 25yrs outdoors, or a history of nonmelanoma skin cancer (NMSC). There has been conflicting evidence as to whether alcohol and smoking independently increase the risk of AC.AC is caused by chronic and excessive exposure to ultraviolet radiation in sunlight.

Risk factors include

  • Outdoor lifestyle – e.g. farmers, sailors, fishermen, windsurfers, mountaineers, golfers, etc.[rx] This has given rise to synonyms for this condition such as “sailor’s lip” and “farmer’s lip”.[rx] The prevalence in agricultural workers in a semi-arid region of Brazil is reported to be 16.7%.[rx]
  • Light skin complexion – the condition typically affects individuals with lighter skin tones,[rx] particularly Caucasians living in tropical regions.[rx] In one report, 96% of persons with AC had phenotype II according to the Fitzpatrick scale.[rx]
  • Age – AC typically affects older individuals, and rarely those under the age of 45.
  • Gender – the condition affects males more commonly than females. Sometimes this ratio is reported as high as 10:1. Additional factors may also play a role, including tobacco use, lip irritation, poor oral hygiene, and ill-fitting dentures.[rx]

Symptoms of Actinic Cheilitis

AC almost always affects the lower lip and only rarely the upper lip, probably because the lower lip is more exposed to the sun. In the unusual cases reported where it affects the upper lip, this may be due to upper lip prominence. The commissures (corners of the mouth) are not usually involved.[rx][rx]

  • Affected individuals may experience symptoms such as a dry sensation and cracking of the lips.[rx] It is usually painless and persistent.
  • The appearance is variable. White lesions indicate hyperkeratosis. Red, erosive or ulcerative lesions indicate atrophy, loss of epithelium, and inflammation. Early, acute lesions may be erythematous (red) and edematous (swollen). With months and years of sun exposure, the lesion becomes chronic and may be grey-white in color and appear dry, scaly, and wrinkled.[rx]
  • There is thickening whitish discoloration of the lip at the border of the lip and skin. There is also a loss of the usually sharp border between the red of the lip and the normal skin, known as the vermillion border. The lip may become scaly and indurated as AC progresses.
  • When palpated, the lip may have a texture similar to rubbing the gloved finger along with sandpaper.[rx]
  • AC may occur with skin lesions of actinic keratosis or skin cancer elsewhere, particularly on the head and neck[rx] since these are the most sun-exposed areas. Rarely it may represent a genetic susceptibility to light damage (e.g. xeroderma pigmentosum or actinic prurigo).[rx]

Diagnosis of Sailor’s Lip

Biopsy w/ H&E is recommended for persistent suspicious lip lesions to rule out invasive skin cancer. Basic histopathology for actinic cheilitis would be:

  • Hyperkeratosis: thickening of stratum corneum
  • Solar elastosis:  loss of eosin staining, accumulation of irregular thick elastic fibers and tangled fibrillin
  • Epithelial dysplasia (mild-moderate): disordered maturation of epidermal cells, loss of rete ridges, variable cytological atypia
  • Perivascular inflammation: inflammatory cells around the blood vessels
  • Severe dysplasia: increase in dyskeratosis, keratin pearls, drop-shaped projections, and nuclei related changes such as mitoses and pleomorphism indicate the progression of dysplasia and increased malignant transformation.

History and Physical

  • Persistent white plaque with “sandpapery” feel on the lips
  • Most commonly lower lip
  • Blurring of the vermillion border between the cutaneous and mucosal lip
  • Usually asymptomatic/painless, but may have burning, numbness, pain
  • Eventually, plaque may become indurated, scaly and ulcerate as lesion progresses
  • Outdoor laborers: sailors, farmers, construction workers, lifeguards
  • Fitzpatrick I-II fair-skinned individuals

Evaluation

Actinic cheilitis is a diagnosis made from clinical and histopathology evaluation. It is essential to distinguish between cheilitis (benign inflammation),  premalignant actinic cheilitis, and squamous cell carcinoma. Skin biopsy is the golden standard regarding the evaluation of a persistent suspicious lesion on the lip. Many lesions initially thought to be premalignant actinic cheilitis on exam were found to be SCC upon histological evaluation, which indicates providers are not able to entirely make the diagnosis clinically, and biopsy is helpful when evaluating these lesions. While not required to make a diagnosis, one article suggests evaluating patients with electron microscopy helps to assess further the ultrastructural changes found in AC lesions, their potential for malignant transformation, and ensure they are diagnosed and managed correctly.

  • Physical exam – persistent white/erythematous thickening sandpapery skin on the lower lip
  • Labwork – for lesions that are new, symmetric, in young patients, found in patient’s with darker skin types, or individuals without a history of chronic sun exposure where skin cancer is less likely, consider first ruling out reversible causes such as those with a vitamin deficiency/infectious/contact/irritant etiology (Chart 1)
  • Skin biopsy – skin biopsy is recommended for persistent lesions
  • Electron Microscopy – hyperkeratosis, mild acanthosis, Perivascular lymphocytic infiltrate around glandular ducts

Treatment of Sailor’s Lip

MEDICAL OPTIONS

  • Topical treatments (ie, chemotherapeutic versus immunotherapy)
  • Topical 5-Fluourouracil
  • Imiquimod
  • Trichloroacetic Acid Peel 50%

SURGICAL

  • Localized shave removal
  • Vermilionectomy

PHYSICAL MODALITIES

  • Cryotherapy
  • Electrosurgery
  • CO2 laser resurfacing
  • Er:YAG laser resurfacing
  • Photodynamic therapy (PDT)
  • Dermabrasion

Treatment of actinic cheilitis should depend on the size, location, and severity of the lesion, along with the patient’s other comorbidities. The goal of therapy is to reduce the risk of malignant transformation from AC to SCC while maintaining functionality and cosmesis of the lips. A variety of therapies targeted at removing the dysplastic epithelium have been used to manage AC, including both surgical and medical options.

Surgical/destructive options for treatment include excisional vermilionectomy, cryotherapy, electrocautery, and pulse-dye or CO2 laser. However, these procedures are invasive, and patients may experience adverse effects such as pain, delayed healing, infection, scarring, edema, and paresthesias.

Non-surgical treatments for AC include topical therapies such as 5-fluorouracil, imiquimod, trichloroacetic acid, ingenol mebutate, diclofenac, phototherapy, topical DNA enzyme repair creams, photoprotection, and curettage with methyl aminolevulinate cream/daylight PDT. Many of the topical treatments cause adverse effects such as inflammation, crusting, and pain, which may reduce patient compliance.

A systemic review and meta-analysis of 283 patients showed surgically treated lesions compared to medically managed lesions had a higher remission rate (92.8% vs. 65%) and lower recurrence rates (8.4 vs. 19.2%) than non-surgical treatment. Dermoscopy has been used to aid with diagnosis and monitor treatment management in patients undergoing topical treatment.

It is difficult to directly compare efficacy across the numerous treatment options available for actinic cheilitis since many of the published studies, the severity of actinic cheilitis, and treatment regimens are not consistent or controlled across studies. However, the following options may be an option when deciding management for actinic cheilitis.

Laser treatment: preferred non-surgical intervention (efficacy 93%, low recurrences)

  • CO2 Laser: 10600 nm
  • Erbium Laser: 2940 nm
  • Adverse effects: pain, hypertrophic scarring (managed with corticosteroids)

Vermilionectomy/Surgical excision – preferred treatment for severe/refractory cases (efficacy near 100%, low recurrences).

  • Adverse effects: pain, delayed healing, infection, scarring, edema, paresthesias, may be cosmetically disfiguring compared to other treatment options

Topical Treatments – preferred treatment for patients with large areas of sun damage or those preferring medical intervention

  • Various treatment regimens studied, examples range from applying to affected area once daily for 1 to 4 weeks depending on patient’s tolerability (Efficacy for 5-FU at one week 69%, increased to 91% efficacy at four weeks)
  • Adverse effects: pain, crusting, inflammation, reduced patient compliance
  • Summary of Topical Options and Their Mechanism of Action

    • 5-FU: impairs pyrimidine thymidine synthesis and DNA replication
    • Imiquimod: nucleoside analog and immunostimulator
    • Ingenol mebutate: induces cell death and neutrophil-mediated antibody-dependent immune response to clear tumors
    • Trichloroacetic acid: induces cell necrosis
    • Diclofenac: anti-inflammatory, induces apoptosis by inhibiting COX 1 and COX2

Phototherapy – while actinic cheilitis results from by UV light damaging epithelial DNA, light therapy at an increased intensity level that causes reactive oxygen species to destroy damaged skin cells and was found to be an effective treatment in some cases (efficacy 68%,12% recurrences). Efficacy increases when used in conjunction with other treatment options, including topical treatments.

  • Adverse effects include pain, recurrence

Cryotherapy – liquid nitrogen physically destroys abnormal cells

  • Adverse effects include pain, crusting, scarring, reduced efficacy compared to other treatment options

Electrocautery/Curettage – physical destruction of the abnormal cells

  • Adverse effects include pain, scarring

Photoprotection – reduce the progression

  •  Dependent on patient compliance

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 the treatment of actinic cheilitis with cryosurgery.

Electrosurgery and localized shave removal are also effective options for discrete areas of actinic cheilitis. Both procedures involve the destruction or removal of clinically involved areas of actinic damage. A local anesthetic is required. Shave removal provides a 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 a 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 super pulsed mode has fewer potential side effects than the continuous waveform. The super pulsed mode reduces the potential for collateral damage by concentrating the energy into rapid pulses with adequate cooling between pulses. The ultra pulsed 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 Sharpton 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 the need for frequent soaks and the 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, valacyclovir 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 a 2940-nm wavelength that targets water and also leads to the 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) passes and coagulation (<1J/cm2, with pulse width between 2-35 ms) pass was 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 a visualization of the 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 the 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-fluorouracil and imiquimod) have been successful at treating actinic cheilitis as they offer a non-surgical option for field treatment. Both are potentially effective treatments, but they are limited by the low rate of patient compliance.

5-fluorouracil (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 the 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. The 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 a topical steroid application. Reactions can be severe and intolerable for patients because of the duration of treatment and impact on the 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 the 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 of 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 the 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 a visualization of the dermis with a dull appearance and pinpoints 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 a clinical recurrence and 100% had a histologic recurrence of dysplasia. Reepithelialization can take 1-3 weeks. Potential side effects include mild discomfort, crusting, edema, and herpes labialis reactivation.

References

Lip Inflammation – Causes, Symptoms, Diagnosis, Treatment

Lip Inflammation/Actinic cheilitis is cheilitis (lip inflammation) caused by long term sunlight exposure. Essentially it is a burn, and a variant of actinic keratosis which occurs on the lip.[rx] It is a premalignant condition,[x] as it can develop into squamous cell carcinoma (a type of mouth cancer).

“Sailor’s Lip,” or actinic cheilitis (AC), is a precursor of squamous cell carcinoma (SCC) found on the lips. Similar to actinic keratosis, actinic cheilitis is a premalignant lesion caused by chronic sun exposure. It is most common on the lower lip along the vermillion border. Given SCC on the lips is considered a high-risk form of skin cancer with an 11% chance of metastasis compared to 1% for other body locations, it is essential to recognize and appropriately manage these potentially malignant precursory lesions.

Actinic cheilitis, also known as solar cheilosis, farmer’s lip, or sailor’s lip, is a reaction to long-term sun exposure on the lips, primarily the lower lip. The lip is especially susceptible to UV radiation because it has a thinner epithelium and less pigment. Some believe actinic cheilitis represents a type of actinic keratosis and is therefore premalignant. Others believe it is a form of in-situ squamous cell carcinoma. Regardless, the literature is in agreement that its presence indicates an increased risk for invasive squamous cell carcinoma.

Pathophysiology

Those with fair skin have less melanin and innately less protection against UV rays. The physical properties of the lips, such as their shape and being a transition area from oral mucosa to skin with thinner epithelium, less sebaceous glands, and less melanin, contribute to less protection and increased exposure to UV radiation. Chronic exposure to UV light damages tumor suppressor gene p53 resulting in uncontrolled replication of defective cells, which is a common gene mutation found with increasing frequency as actinic cheilitis and actinic keratoses undergo malignant transformation to SCC. Although actinic cheilitis can affect both the upper and lower oral cutaneous mucosa, more light from the sun hits the lower lip, making this area especially prone to sun damage and an increased number of skin cancers.

Causes of Actinic Cheilitis

Actinic cheilitis results from the sun or UV radiation exposure. Additional risk factors include increased age, especially over 60 years, Fitzpatrick I and II skin types, genetic abnormalities affecting pigmentation such as albinism, working more than 25yrs outdoors, or a history of nonmelanoma skin cancer (NMSC). There has been conflicting evidence as to whether alcohol and smoking independently increase the risk of AC.AC is caused by chronic and excessive exposure to ultraviolet radiation in sunlight.

Risk factors include

  • Outdoor lifestyle – e.g. farmers, sailors, fishermen, windsurfers, mountaineers, golfers, etc.[rx] This has given rise to synonyms for this condition such as “sailor’s lip” and “farmer’s lip”.[rx] The prevalence in agricultural workers in a semi-arid region of Brazil is reported to be 16.7%.[rx]
  • Light skin complexion – the condition typically affects individuals with lighter skin tones,[rx] particularly Caucasians living in tropical regions.[rx] In one report, 96% of persons with AC had phenotype II according to the Fitzpatrick scale.[rx]
  • Age – AC typically affects older individuals, and rarely those under the age of 45.
  • Gender – the condition affects males more commonly than females. Sometimes this ratio is reported as high as 10:1. Additional factors may also play a role, including tobacco use, lip irritation, poor oral hygiene, and ill-fitting dentures.[rx]

Symptoms of Actinic Cheilitis

AC almost always affects the lower lip and only rarely the upper lip, probably because the lower lip is more exposed to the sun. In the unusual cases reported where it affects the upper lip, this may be due to upper lip prominence. The commissures (corners of the mouth) are not usually involved.[rx][rx]

  • Affected individuals may experience symptoms such as a dry sensation and cracking of the lips.[rx] It is usually painless and persistent.
  • The appearance is variable. White lesions indicate hyperkeratosis. Red, erosive or ulcerative lesions indicate atrophy, loss of epithelium, and inflammation. Early, acute lesions may be erythematous (red) and edematous (swollen). With months and years of sun exposure, the lesion becomes chronic and may be grey-white in color and appear dry, scaly, and wrinkled.[rx]
  • There is thickening whitish discoloration of the lip at the border of the lip and skin. There is also a loss of the usually sharp border between the red of the lip and the normal skin, known as the vermillion border. The lip may become scaly and indurated as AC progresses.
  • When palpated, the lip may have a texture similar to rubbing the gloved finger along with sandpaper.[rx]
  • AC may occur with skin lesions of actinic keratosis or skin cancer elsewhere, particularly on the head and neck[rx] since these are the most sun-exposed areas. Rarely it may represent a genetic susceptibility to light damage (e.g. xeroderma pigmentosum or actinic prurigo).[rx]

Diagnosis of Actinic Cheilitis

Biopsy w/ H&E is recommended for persistent suspicious lip lesions to rule out invasive skin cancer. Basic histopathology for actinic cheilitis would be:

  • Hyperkeratosis: thickening of stratum corneum
  • Solar elastosis:  loss of eosin staining, accumulation of irregular thick elastic fibers and tangled fibrillin
  • Epithelial dysplasia (mild-moderate): disordered maturation of epidermal cells, loss of rete ridges, variable cytological atypia
  • Perivascular inflammation: inflammatory cells around the blood vessels
  • Severe dysplasia: increase in dyskeratosis, keratin pearls, drop-shaped projections, and nuclei related changes such as mitoses and pleomorphism indicate the progression of dysplasia and increased malignant transformation.

History and Physical

  • Persistent white plaque with “sandpapery” feel on the lips
  • Most commonly lower lip
  • Blurring of the vermillion border between the cutaneous and mucosal lip
  • Usually asymptomatic/painless, but may have burning, numbness, pain
  • Eventually, plaque may become indurated, scaly and ulcerate as lesion progresses
  • Outdoor laborers: sailors, farmers, construction workers, lifeguards
  • Fitzpatrick I-II fair-skinned individuals

Evaluation

Actinic cheilitis is a diagnosis made from clinical and histopathology evaluation. It is essential to distinguish between cheilitis (benign inflammation),  premalignant actinic cheilitis, and squamous cell carcinoma. Skin biopsy is the golden standard regarding the evaluation of a persistent suspicious lesion on the lip. Many lesions initially thought to be premalignant actinic cheilitis on exam were found to be SCC upon histological evaluation, which indicates providers are not able to entirely make the diagnosis clinically, and biopsy is helpful when evaluating these lesions. While not required to make a diagnosis, one article suggests evaluating patients with electron microscopy helps to assess further the ultrastructural changes found in AC lesions, their potential for malignant transformation, and ensure they are diagnosed and managed correctly.

  • Physical exam – persistent white/erythematous thickening sandpapery skin on the lower lip
  • Labwork – for lesions that are new, symmetric, in young patients, found in patient’s with darker skin types, or individuals without a history of chronic sun exposure where skin cancer is less likely, consider first ruling out reversible causes such as those with a vitamin deficiency/infectious/contact/irritant etiology (Chart 1)
  • Skin biopsy – skin biopsy is recommended for persistent lesions
  • Electron Microscopy – hyperkeratosis, mild acanthosis, Perivascular lymphocytic infiltrate around glandular ducts

Treatment of Actinic Cheilitis

MEDICAL OPTIONS

  • Topical treatments (ie, chemotherapeutic versus immunotherapy)
  • Topical 5-Fluourouracil
  • Imiquimod
  • Trichloroacetic Acid Peel 50%

SURGICAL

  • Localized shave removal
  • Vermilionectomy

PHYSICAL MODALITIES

  • Cryotherapy
  • Electrosurgery
  • CO2 laser resurfacing
  • Er:YAG laser resurfacing
  • Photodynamic therapy (PDT)
  • Dermabrasion

Treatment of actinic cheilitis should depend on the size, location, and severity of the lesion, along with the patient’s other comorbidities. The goal of therapy is to reduce the risk of malignant transformation from AC to SCC while maintaining functionality and cosmesis of the lips. A variety of therapies targeted at removing the dysplastic epithelium have been used to manage AC, including both surgical and medical options.

Surgical/destructive options for treatment include excisional vermilionectomy, cryotherapy, electrocautery, and pulse-dye or CO2 laser. However, these procedures are invasive, and patients may experience adverse effects such as pain, delayed healing, infection, scarring, edema, and paresthesias.

Non-surgical treatments for AC include topical therapies such as 5-fluorouracil, imiquimod, trichloroacetic acid, ingenol mebutate, diclofenac, phototherapy, topical DNA enzyme repair creams, photoprotection, and curettage with methyl aminolevulinate cream/daylight PDT. Many of the topical treatments cause adverse effects such as inflammation, crusting, and pain, which may reduce patient compliance.

A systemic review and meta-analysis of 283 patients showed surgically treated lesions compared to medically managed lesions had a higher remission rate (92.8% vs. 65%) and lower recurrence rates (8.4 vs. 19.2%) than non-surgical treatment. Dermoscopy has been used to aid with diagnosis and monitor treatment management in patients undergoing topical treatment.

It is difficult to directly compare efficacy across the numerous treatment options available for actinic cheilitis since many of the published studies, the severity of actinic cheilitis, and treatment regimens are not consistent or controlled across studies. However, the following options may be an option when deciding management for actinic cheilitis.

Laser treatment: preferred non-surgical intervention (efficacy 93%, low recurrences)

  • CO2 Laser: 10600 nm
  • Erbium Laser: 2940 nm
  • Adverse effects: pain, hypertrophic scarring (managed with corticosteroids)

Vermilionectomy/Surgical excision – preferred treatment for severe/refractory cases (efficacy near 100%, low recurrences).

  • Adverse effects: pain, delayed healing, infection, scarring, edema, paresthesias, may be cosmetically disfiguring compared to other treatment options

Topical Treatments – preferred treatment for patients with large areas of sun damage or those preferring medical intervention

  • Various treatment regimens studied, examples range from applying to affected area once daily for 1 to 4 weeks depending on patient’s tolerability (Efficacy for 5-FU at one week 69%, increased to 91% efficacy at four weeks)
  • Adverse effects: pain, crusting, inflammation, reduced patient compliance
  • Summary of Topical Options and Their Mechanism of Action

    • 5-FU: impairs pyrimidine thymidine synthesis and DNA replication
    • Imiquimod: nucleoside analog and immunostimulator
    • Ingenol mebutate: induces cell death and neutrophil-mediated antibody-dependent immune response to clear tumors
    • Trichloroacetic acid: induces cell necrosis
    • Diclofenac: anti-inflammatory, induces apoptosis by inhibiting COX 1 and COX2

Phototherapy – while actinic cheilitis results from by UV light damaging epithelial DNA, light therapy at an increased intensity level that causes reactive oxygen species to destroy damaged skin cells and was found to be an effective treatment in some cases (efficacy 68%,12% recurrences). Efficacy increases when used in conjunction with other treatment options, including topical treatments.

  • Adverse effects include pain, recurrence

Cryotherapy – liquid nitrogen physically destroys abnormal cells

  • Adverse effects include pain, crusting, scarring, reduced efficacy compared to other treatment options

Electrocautery/Curettage – physical destruction of the abnormal cells

  • Adverse effects include pain, scarring

Photoprotection – reduce the progression

  •  Dependent on patient compliance

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 the treatment of actinic cheilitis with cryosurgery.

Electrosurgery and localized shave removal are also effective options for discrete areas of actinic cheilitis. Both procedures involve the destruction or removal of clinically involved areas of actinic damage. A local anesthetic is required. Shave removal provides a 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 a 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 super pulsed mode has fewer potential side effects than the continuous waveform. The super pulsed mode reduces the potential for collateral damage by concentrating the energy into rapid pulses with adequate cooling between pulses. The ultra pulsed 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 Sharpton 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 the need for frequent soaks and the 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, valacyclovir 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 a 2940-nm wavelength that targets water and also leads to the 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) passes and coagulation (<1J/cm2, with pulse width between 2-35 ms) pass was 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 a visualization of the 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 the 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-fluorouracil and imiquimod) have been successful at treating actinic cheilitis as they offer a non-surgical option for field treatment. Both are potentially effective treatments, but they are limited by the low rate of patient compliance.

5-fluorouracil (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 the 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. The 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 a topical steroid application. Reactions can be severe and intolerable for patients because of the duration of treatment and impact on the 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 the 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 of 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 the 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 a visualization of the dermis with a dull appearance and pinpoints 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 a clinical recurrence and 100% had a histologic recurrence of dysplasia. Reepithelialization can take 1-3 weeks. Potential side effects include mild discomfort, crusting, edema, and herpes labialis reactivation.

References

Actinic Cheilitis – Causes, Symptoms, Diagnosis, Treatment

Actinic cheilitis is cheilitis (lip inflammation) caused by long term sunlight exposure. Essentially it is a burn, and a variant of actinic keratosis which occurs on the lip.[rx] It is a premalignant condition,[x] as it can develop into squamous cell carcinoma (a type of mouth cancer).

“Sailor’s Lip,” or actinic cheilitis (AC), is a precursor of squamous cell carcinoma (SCC) found on the lips. Similar to actinic keratosis, actinic cheilitis is a premalignant lesion caused by chronic sun exposure. It is most common on the lower lip along the vermillion border. Given SCC on the lips is considered a high-risk form of skin cancer with an 11% chance of metastasis compared to 1% for other body locations, it is essential to recognize and appropriately manage these potentially malignant precursory lesions.

Actinic cheilitis, also known as solar cheilosis, farmer’s lip, or sailor’s lip, is a reaction to long-term sun exposure on the lips, primarily the lower lip. The lip is especially susceptible to UV radiation because it has a thinner epithelium and less pigment. Some believe actinic cheilitis represents a type of actinic keratosis and is therefore premalignant. Others believe it is a form of in-situ squamous cell carcinoma. Regardless, the literature is in agreement that its presence indicates an increased risk for invasive squamous cell carcinoma.

Pathophysiology

Those with fair skin have less melanin and innately less protection against UV rays. The physical properties of the lips, such as their shape and being a transition area from oral mucosa to skin with thinner epithelium, less sebaceous glands, and less melanin, contribute to less protection and increased exposure to UV radiation. Chronic exposure to UV light damages tumor suppressor gene p53 resulting in uncontrolled replication of defective cells, which is a common gene mutation found with increasing frequency as actinic cheilitis and actinic keratoses undergo malignant transformation to SCC. Although actinic cheilitis can affect both the upper and lower oral cutaneous mucosa, more light from the sun hits the lower lip, making this area especially prone to sun damage and an increased number of skin cancers.

Causes of Actinic Cheilitis

Actinic cheilitis results from the sun or UV radiation exposure. Additional risk factors include increased age, especially over 60 years, Fitzpatrick I and II skin types, genetic abnormalities affecting pigmentation such as albinism, working more than 25yrs outdoors, or a history of nonmelanoma skin cancer (NMSC). There has been conflicting evidence as to whether alcohol and smoking independently increase the risk of AC.AC is caused by chronic and excessive exposure to ultraviolet radiation in sunlight.

Risk factors include

  • Outdoor lifestyle – e.g. farmers, sailors, fishermen, windsurfers, mountaineers, golfers, etc.[rx] This has given rise to synonyms for this condition such as “sailor’s lip” and “farmer’s lip”.[rx] The prevalence in agricultural workers in a semi-arid region of Brazil is reported to be 16.7%.[rx]
  • Light skin complexion – the condition typically affects individuals with lighter skin tones,[rx] particularly Caucasians living in tropical regions.[rx] In one report, 96% of persons with AC had phenotype II according to the Fitzpatrick scale.[rx]
  • Age – AC typically affects older individuals, and rarely those under the age of 45.
  • Gender – the condition affects males more commonly than females. Sometimes this ratio is reported as high as 10:1. Additional factors may also play a role, including tobacco use, lip irritation, poor oral hygiene, and ill-fitting dentures.[rx]

Symptoms of Actinic Cheilitis

AC almost always affects the lower lip and only rarely the upper lip, probably because the lower lip is more exposed to the sun. In the unusual cases reported where it affects the upper lip, this may be due to upper lip prominence. The commissures (corners of the mouth) are not usually involved.[rx][rx]

  • Affected individuals may experience symptoms such as a dry sensation and cracking of the lips.[rx] It is usually painless and persistent.
  • The appearance is variable. White lesions indicate hyperkeratosis. Red, erosive or ulcerative lesions indicate atrophy, loss of epithelium, and inflammation. Early, acute lesions may be erythematous (red) and edematous (swollen). With months and years of sun exposure, the lesion becomes chronic and may be grey-white in color and appear dry, scaly, and wrinkled.[rx]
  • There is thickening whitish discoloration of the lip at the border of the lip and skin. There is also a loss of the usually sharp border between the red of the lip and the normal skin, known as the vermillion border. The lip may become scaly and indurated as AC progresses.
  • When palpated, the lip may have a texture similar to rubbing the gloved finger along with sandpaper.[rx]
  • AC may occur with skin lesions of actinic keratosis or skin cancer elsewhere, particularly on the head and neck[rx] since these are the most sun-exposed areas. Rarely it may represent a genetic susceptibility to light damage (e.g. xeroderma pigmentosum or actinic prurigo).[rx]

Diagnosis of Actinic Cheilitis

Biopsy w/ H&E is recommended for persistent suspicious lip lesions to rule out invasive skin cancer. Basic histopathology for actinic cheilitis would be:

  • Hyperkeratosis: thickening of stratum corneum
  • Solar elastosis:  loss of eosin staining, accumulation of irregular thick elastic fibers and tangled fibrillin
  • Epithelial dysplasia (mild-moderate): disordered maturation of epidermal cells, loss of rete ridges, variable cytological atypia
  • Perivascular inflammation: inflammatory cells around the blood vessels
  • Severe dysplasia: increase in dyskeratosis, keratin pearls, drop-shaped projections, and nuclei related changes such as mitoses and pleomorphism indicate the progression of dysplasia and increased malignant transformation.

History and Physical

  • Persistent white plaque with “sandpapery” feel on the lips
  • Most commonly lower lip
  • Blurring of the vermillion border between the cutaneous and mucosal lip
  • Usually asymptomatic/painless, but may have burning, numbness, pain
  • Eventually, plaque may become indurated, scaly and ulcerate as lesion progresses
  • Outdoor laborers: sailors, farmers, construction workers, lifeguards
  • Fitzpatrick I-II fair-skinned individuals

Evaluation

Actinic cheilitis is a diagnosis made from clinical and histopathology evaluation. It is essential to distinguish between cheilitis (benign inflammation),  premalignant actinic cheilitis, and squamous cell carcinoma. Skin biopsy is the golden standard regarding the evaluation of a persistent suspicious lesion on the lip. Many lesions initially thought to be premalignant actinic cheilitis on exam were found to be SCC upon histological evaluation, which indicates providers are not able to entirely make the diagnosis clinically, and biopsy is helpful when evaluating these lesions. While not required to make a diagnosis, one article suggests evaluating patients with electron microscopy helps to assess further the ultrastructural changes found in AC lesions, their potential for malignant transformation, and ensure they are diagnosed and managed correctly.

  • Physical exam – persistent white/erythematous thickening sandpapery skin on the lower lip
  • Labwork – for lesions that are new, symmetric, in young patients, found in patient’s with darker skin types, or individuals without a history of chronic sun exposure where skin cancer is less likely, consider first ruling out reversible causes such as those with a vitamin deficiency/infectious/contact/irritant etiology (Chart 1)
  • Skin biopsy – skin biopsy is recommended for persistent lesions
  • Electron Microscopy – hyperkeratosis, mild acanthosis, Perivascular lymphocytic infiltrate around glandular ducts

Treatment of Actinic Cheilitis

MEDICAL OPTIONS

  • Topical treatments (ie, chemotherapeutic versus immunotherapy)
  • Topical 5-Fluourouracil
  • Imiquimod
  • Trichloroacetic Acid Peel 50%

SURGICAL

  • Localized shave removal
  • Vermilionectomy

PHYSICAL MODALITIES

  • Cryotherapy
  • Electrosurgery
  • CO2 laser resurfacing
  • Er:YAG laser resurfacing
  • Photodynamic therapy (PDT)
  • Dermabrasion

Treatment of actinic cheilitis should depend on the size, location, and severity of the lesion, along with the patient’s other comorbidities. The goal of therapy is to reduce the risk of malignant transformation from AC to SCC while maintaining functionality and cosmesis of the lips. A variety of therapies targeted at removing the dysplastic epithelium have been used to manage AC, including both surgical and medical options.

Surgical/destructive options for treatment include excisional vermilionectomy, cryotherapy, electrocautery, and pulse-dye or CO2 laser. However, these procedures are invasive, and patients may experience adverse effects such as pain, delayed healing, infection, scarring, edema, and paresthesias.

Non-surgical treatments for AC include topical therapies such as 5-fluorouracil, imiquimod, trichloroacetic acid, ingenol mebutate, diclofenac, phototherapy, topical DNA enzyme repair creams, photoprotection, and curettage with methyl aminolevulinate cream/daylight PDT. Many of the topical treatments cause adverse effects such as inflammation, crusting, and pain, which may reduce patient compliance.

A systemic review and meta-analysis of 283 patients showed surgically treated lesions compared to medically managed lesions had a higher remission rate (92.8% vs. 65%) and lower recurrence rates (8.4 vs. 19.2%) than non-surgical treatment. Dermoscopy has been used to aid with diagnosis and monitor treatment management in patients undergoing topical treatment.

It is difficult to directly compare efficacy across the numerous treatment options available for actinic cheilitis since many of the published studies, the severity of actinic cheilitis, and treatment regimens are not consistent or controlled across studies. However, the following options may be an option when deciding management for actinic cheilitis.

Laser treatment: preferred non-surgical intervention (efficacy 93%, low recurrences)

  • CO2 Laser: 10600 nm
  • Erbium Laser: 2940 nm
  • Adverse effects: pain, hypertrophic scarring (managed with corticosteroids)

Vermilionectomy/Surgical excision – preferred treatment for severe/refractory cases (efficacy near 100%, low recurrences).

  • Adverse effects: pain, delayed healing, infection, scarring, edema, paresthesias, may be cosmetically disfiguring compared to other treatment options

Topical Treatments – preferred treatment for patients with large areas of sun damage or those preferring medical intervention

  • Various treatment regimens studied, examples range from applying to affected area once daily for 1 to 4 weeks depending on patient’s tolerability (Efficacy for 5-FU at one week 69%, increased to 91% efficacy at four weeks)
  • Adverse effects: pain, crusting, inflammation, reduced patient compliance
  • Summary of Topical Options and Their Mechanism of Action

    • 5-FU: impairs pyrimidine thymidine synthesis and DNA replication
    • Imiquimod: nucleoside analog and immunostimulator
    • Ingenol mebutate: induces cell death and neutrophil-mediated antibody-dependent immune response to clear tumors
    • Trichloroacetic acid: induces cell necrosis
    • Diclofenac: anti-inflammatory, induces apoptosis by inhibiting COX 1 and COX2

Phototherapy – while actinic cheilitis results from by UV light damaging epithelial DNA, light therapy at an increased intensity level that causes reactive oxygen species to destroy damaged skin cells and was found to be an effective treatment in some cases (efficacy 68%,12% recurrences). Efficacy increases when used in conjunction with other treatment options, including topical treatments.

  • Adverse effects include pain, recurrence

Cryotherapy – liquid nitrogen physically destroys abnormal cells

  • Adverse effects include pain, crusting, scarring, reduced efficacy compared to other treatment options

Electrocautery/Curettage – physical destruction of the abnormal cells

  • Adverse effects include pain, scarring

Photoprotection – reduce the progression

  •  Dependent on patient compliance

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 the treatment of actinic cheilitis with cryosurgery.

Electrosurgery and localized shave removal are also effective options for discrete areas of actinic cheilitis. Both procedures involve the destruction or removal of clinically involved areas of actinic damage. A local anesthetic is required. Shave removal provides a 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 a 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 super pulsed mode has fewer potential side effects than the continuous waveform. The super pulsed mode reduces the potential for collateral damage by concentrating the energy into rapid pulses with adequate cooling between pulses. The ultra pulsed 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 Sharpton 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 the need for frequent soaks and the 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, valacyclovir 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 a 2940-nm wavelength that targets water and also leads to the 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) passes and coagulation (<1J/cm2, with pulse width between 2-35 ms) pass was 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 a visualization of the 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 the 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-fluorouracil and imiquimod) have been successful at treating actinic cheilitis as they offer a non-surgical option for field treatment. Both are potentially effective treatments, but they are limited by the low rate of patient compliance.

5-fluorouracil (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 the 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. The 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 a topical steroid application. Reactions can be severe and intolerable for patients because of the duration of treatment and impact on the 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 the 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 of 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 the 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 a visualization of the dermis with a dull appearance and pinpoints 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 a clinical recurrence and 100% had a histologic recurrence of dysplasia. Reepithelialization can take 1-3 weeks. Potential side effects include mild discomfort, crusting, edema, and herpes labialis reactivation.

References

What Is Cheilitis? – Symptoms, Causes, Treatment

What Is Cheilitis?/Cheilitis is an inflammation of the lips, which could be acute or chronic. The inflammation primarily arises in the vermilion zone but may extend to surrounding skin and less commonly, to the oral mucosa. It may be caused by a multitude of factors, including contact irritants or allergens, chronic sun exposure, and nutritional deficiencies, as well as by various cutaneous and systemic illnesses.

Cheilitis is inflammation of the lips. This inflammation may include the perioral skin (the skin around the mouth), the vermilion border, or the labial mucosa. The skin and the vermilion border are more commonly involved, as the mucosa is less affected by inflammatory and allergic reactions.[rx]

Types of Cheilitis

It is a general term, and there are many recognized types and different causes. Cheilitis can be either acute or chronic. Most cheilitis is caused by exogenous factors such as dryness (chapping) and acute sun exposure.[rx] Patch testing may identify allergens that cause cheilitis.[rx]

The lips can be inflamed because of an infection or skin condition

  • Herpes simplex
  • Angular cheilitis
  • Granulomatous cheilitis
  • Orofacial granulomatosis
  • Crohn skin disease
  • Actinic cheilitis
  • Exfoliative cheilitis
  • Glandular cheilitis
  • Lichenoid cheilitis
  • Cutaneous lupus erythematosus

They may be inflamed because of an allergytoxin, medication or injury.

  • Eczematous cheilitis
  • Allergic contact cheilitis
  • Pigmented contact cheilitis
  • Cheilitis in musicians
  • Contact reactions to lipsticks and other lip care products
  • Irritant contact dermatitis
  • Allergic contact dermatitis
  • Smoking and its effects on the skin
  • Sunburn
  • Isotretinoin treatment
  • Acitretin treatment
  • Denture stomatitis

Eczematous cheilitis most common form of cheilitis and is more prevalent in people with a history of allergies. 

  • Angular cheilitis/infective cheilitis – may present at any age with an equal male to female ratio but is especially likely in older individuals wearing dentures. Children suffering from these forms have a history of recurrent infections or immune defects.
  • Actinic cheilitis – is more prevalent in geographic areas with high ultraviolet (UV) irradiation, and in fair-skinned men who work outdoors (e.g., fishermen, farmers) in their fourth to the eighth decade of life. Certain genetic conditions associated with increased susceptibility to solar damage may predispose individuals to acquire actinic cheilitis at an early age (e.g., xeroderma pigmentosum, oculocutaneous albinism).
  • Glandular cheilitis – is a rare form of cheilitis, more prevalent in older males, but individuals in younger age and women also may be affected. The cause is unknown, but several factors have been identified, including atopy, infection, chronic exposure to the sun, repeated licking, and use of tobacco.
  • Cheilitis granulomatosis –  is rare. It primarily affects young adults but can occur at any age, with equal ration in male to female. It is idiopathic. However, there are several predisposing factors, including food allergy, genetics, infection, and atopy.

Causes of Cheilitis

  • Eczematous cheilitis –  could be a result of exogenous factors (irritant contact cheilitis, allergic cheilitis) or endogenous factors (atopic cheilitis).
  • Dry, chapped lips – Frequent exposure to hot or dry winds can cause loss of plasticity of keratin in vermillion, leading to sores and dry, scaly lips. The patient might get into the habit of chronic licking of lips to pick upscales, which further aggravates the problem. It is also referred to as irritant contact cheilitis.
  • Allergic Contact Cheilitis – A delayed-type hypersensitivity reaction to allergens that come in contact with the lips can cause inflammation of the lips. It is also known as lipstick cheilitis since several ingredients found in lipsticks may act as irritants. The most common cosmetic sensitizers identified by patch testing include fragrances, Myroxylon pereirae, and nickel. However, some ingredients unique to lipsticks may also cause lip dermatitis. For example, castor oil, colophony, shellac, azo dyes, sesame oil, preservatives, ozonated olive oil, propolis, and copolymers. Apart from lipsticks, allergic contact cheilitis can be caused by a variety of other substances that come into contact with lips. They could be found in mouthwashes, toothpaste, and even food. Lipstick cheilitis may present as persistent irritation and scaling, sometimes associated with edema and vascularization, confined to vermillion or extending beyond in some cases. Cheilitis caused by food may involve the skin around the mouth.
  • Atopic Cheilitis – Patients with a history of atopy or atopic dermatitis commonly have associated atopic cheilitis. It presents with dryness, erythema, scaling, and fissuring of lips.
  • Angular Cheilitis – Angular cheilitis, also known as angular stomatitis or perlèche, is an acute or chronic inflammation of the skin and adjacent labial mucosa at the angles of the mouth. It manifests as a roughly triangular area of erythema and edema at one, or more frequently both, angles of the mouth. The most common cause of angular cheilitis in adults is a fungal infection, Candida albicans, and less commonly, Staphylococcus aureus. Poor oral hygiene, ill-fitting dentures, or absence of teeth as in the elderly can lead to excessive moisture and maceration from saliva leading to these infections. Less commonly, the nutritional deficiencies, particularly those of riboflavin (B2), niacin (B3), pyridoxine (B6), folate (B9), iron, and general protein malnutrition, may produce smooth, shiny, red lips associated with angular stomatitis, collectively known as cheilosis. 
  • Infective cheilitis – Viral cheilitis: It is mainly due to the herpes simplex virus, especially type 1. The primary herpes infection (herpetic gingivostomatitis) combines post-vesicular erosive and crusted cheilitis with diffuse stomatitis leading to dysphagia, perioral vesicles, fever, and cervical lymphadenopathy. Recurrence of oral herpes affects the lips in most cases. It manifests as a cluster of blisters accompanied by a burning sensation. Next, the vesicles erode to leave behind crusted erosions that resolve in a week.
  • Bacterial Cheilitis – The most common cause of bacterial cheilitis is infection with group A Streptococcus or Staphylococcus.
  • Mycotic cheilitis  Cheilitis caused by candida manifests with erythema and painful edema of the lips, sometimes with fissures, and it is usually accompanied by acute (pseudomembranous candidiasis) or chronic stomatitis, and/or angular cheilitis. The diagnosis is confirmed by taking a specimen for mycological examination.
  • Parasitic cheilitis Leishmaniasis is a possible cause of cheilitis in endemic regions. It gives the appearance of an erythematous papule or plaque that gradually enlarges and then ulcerates or a permanent lip enlargement (macrocheilia).
  • Actinic Cheilitis – Actinic Cheilitis (also known as solar keratosis of the lip or actinic keratosis) originates from the proliferation of atypical epidermal keratinocytes due to chronic sun exposure. It is a premalignant condition and occasionally progresses to squamous cell carcinoma. Most cases are observed in outdoor workers, fair-skinned individuals, and during the fourth to eighth decades of life. The lower lip border receives the highest ultraviolet radiation, being at the right angle to the midday sun rays and poorly protected by melanocytes. Clinical symptoms are varied, depending upon the stage of the disease, and may include erythema, edema, plaques, and nodules and later develop into ulceration as the lesion becomes malignant. Notably, the lesions have a characteristic “sandpapery” feel to touch.
  • Drug-induced cheilitis – Systemic retinoids such as etretinate and isotretinoin cause dryness, erythema, scaling, and cracking of the lips (may include angles of the mouth) in almost all the patients. Less frequently, it may also be caused by any other drugs that cause dryness of mouth and lip.
  • Glandular cheilitis – It is a rare, chronic inflammation with tumefaction and sometimes suppuration of salivary glands at the lower lip. The most common clinical form is the simple cheilitis glandularis, which manifests as a moderate thickening of the lower lip with inflammatory dilated gland duct orifices, from which mucous saliva can be squeezed easily. Older males are most commonly affected, but can also be seen in young individuals and women. In the more severe suppurative form (Volkmann’s cheilitis), the lip is enlarged considerably and persistently (macrocheilia) and is associated with pain and tenderness. Crusts and scales cover the surface, beneath which the salivary duct openings may be found. Eventually, it results in a deep-seated infection that may cause the formation of abscess and fistulous tracts.
  • Cheilitis granulomatosis – Cheilitis granulomatosis is a persistent, idiopathic, nontender granulomatous inflammation of one or both lips. The initial manifestation is sudden diffuse or nodular swellings involving the upper lip, the lower lip, and one or both cheeks in decreasing incidence. Early attacks cause edema of lips that usually subsides in days to hours; however, recurrent attacks may lead to a persistent increase in swelling, leading to firm, rubber-like consistency of lips. Cheilitis granulomatosis can be isolated, idiopathic (Miescher cheilitis granulomatosis), or associated with various systemic conditions (sarcoidosis, Crohn’s disease, tuberculosis). The complete form of Melkersson Rosenthal syndrome combines cheilitis granulomatosis, peripheral facial paralysis, and a fissured tongue with loss of taste sensation.

Listed below are some of the known causes of actinic cheilitis and risk factors for the condition

  • Chronic sun exposure – The more often the lips are exposed to sunlight, the more likely damage is to occur.
  • Severe sunburn – Sunburn further damages skin cells and causes them to divide and regenerate, increasing the chances of cellular mutations.
  • Sex – Three times more men than women develop actinic cheilitis.
  • Fair skin – A majority of those with actinic cheilitis are white or fair-skinned. Rates are very high in people with albinism or those with skin pigment disorders.
  • Tropical, subtropical, or desert environments – Regions near the equator have increased ultraviolet exposure. Tropical and desert regions also typically have more sunny, warm days that encourage being outdoors.
  • Jobs that involve being outdoors – Jobs or hobbies that require being outdoors in the sun for more time increase the risk of sun damage. Lifeguards, construction workers, hikers, marathon runners, farmers, and sailors may have a higher chance of developing actinic cheilitis.
  • Age – Usually the result of chronic or long-term sun damage, the condition mostly impacts adults.
  • Smoking – Smoking or chewing tobacco can weaken lip epithelium and make it more vulnerable to sun damage.
  • Actinic prurigo – This rare, itchy photosensitivity condition causes the skin to be more sensitive to sun damage.
  • Excessive alcohol use.
  • Oncogenic human papillomavirus – the virus that causes warts.
  • Immune disorders or immunosuppressing medications – Medications that weaken and suppress the immune system usually increase the risk of sun damage.
  • Everted lower lip – When the lip is turned more outward instead of inward.

Symptoms of Cheilitis

The main things you’ll notice are irritation and soreness in the corner(s) of your mouth. One or both corners may be:

  • Bleeding
  • Blistered
  • Cracked
  • Crusty
  • Itchy
  • Painful
  • Red
  • Scaly
  • Swollen

Your lips can feel dry and uncomfortable. Sometimes your lips and mouth can feel like they’re burning. You also might have a bad taste in your mouth.

Other symptoms include:

  • bad taste in your mouth
  • burning feeling on your lips or mouth
  • lips feeling dry or chapped
  • difficulty eating as a result of the irritation

Diagnosis of Cheilitis

History and Physical Exam

  • Your physician would take you through a number of questions which might include the history of the onset of the problem, and any underlying or associated complaints or symptoms. The history would include questions about denture history, oral care, other chronic skin conditions, medicine or drug history, the habit of smoking, nutrition and diet, bowel movements, and acid reflux

Evaluation

The diagnosis of most cheilitis is based on clinical signs and a careful anamnesis.

  • The diagnosis of allergic contact cheilitis – is confirmed by a history of allergy and a relevant patch test reaction. Patients with negative patch testing are diagnosed with irritant contact cheilitis or atopic cheilitis.
  • A biopsy is required in cheilitis granulomatosa to confirm the diagnosis. Once the diagnosis of granulomatous cheilitis is made, a thorough etiological assessment is necessary.
  • A biopsy – is also important in chronic actinic cheilitis if there is suspicion of malignant transformation.
    Finally, in the case of allergic cheilitis, an allergy survey is required. It includes a careful history and appropriate allergy tests.
  • Physical Examination – A thorough examination by your physician will help narrow the diagnosis.
  • Lab Investigations – Oral swabs and biopsies help to rule the underlying cause of the disease and confirm the diagnosis. Oral swabs, also known as culture swabs, are done to rule out the infection from candida, staphylococcus bacteria or herpes simplex. A biopsy can help to diagnose a condition a lichen planus or a precancerous lesion.

Treatment of Cheilitis

The therapeutic management of cheilitis is symptomatic and etiological

The goal is to clear out the infection and keep the area dry so your skin isn’t infected again. Your doctor will recommend an antifungal cream to treat fungal infections. Some are:

  • nystatin (Mycostatin)
  • ketoconazole (Extina)
  • clotrimazole (Lotrimin)
  • miconazole (Lotrimin AF, Micatin, Monistat Derm)

If your infection is bacterial, your doctor will prescribe an antibacterial medication, such as:

  • mupirocin (Bactroban)
  • fusidic acid (Fucidin, Fucithalmic)

For someone with uncontrolled diabetes, treatment might include diet and lifestyle changes, insulin therapy, or diabetes medications. Vitamin supplements or changes in diet can help people who develop angular cheilitis due to poor nutrition.

Antibiotics

When the area is infected, then the underlying infection requires treatment. It is important to diagnose the cause of the infection since yeast infections, for example, will not respond to antibiotics. In most cases, a doctor can tell by looking at it whether the infection is bacterial or due to yeast.

Hygiene

Keeping the area clean and dry can ease pain and prevent an infection from worsening. A lip balm or protectant can relieve dryness and protect the skin from saliva. A doctor may also recommend a topical steroid cream, which can be applied to the skin to stimulate healing. A steroid cream may also help with pain and itching.

Fillers and injections

When an issue with the lip or mouth shape makes angular cheilitis more likely, or if a person has had several infections with angular cheilitis, a doctor might recommend treatment to change the shape of the mouth.

Dry, chapped lips – Avoidance of lip sucking, lip balms, or any other causative agent, and the local application of petroleum jelly is helpful.

Allergic contact cheilitis and atopic cheilitis – Excluding the allergen responsible and applying a low to medium intensity topical steroid and emollients. Sometimes a potent steroid (fludrocortisone) or off-label use of topical calcineurin inhibitors may be required.

Angular cheilitis – The treatment is maintaining oral hygiene, using dentures with the proper fit, using barrier creams (eg, zinc oxide paste) or petrolatum and treatment of sicca symptoms. Vitamin supplements could be given in case of nutritional deficiency. In case of cheilitis due to dentures, dentures must be removed before going to bed at night, brushed intensely, and then soaked in a solution of chlorhexidine gluconate or a dilute solution of bleach (10 drops of solution in a denture cup filled with water).

Infective cheilitis – Maintaining proper oral hygiene, and treatment of the underlying cause of infection is indicated. The most common infection is by Candida albicans which has different treatment approaches depending upon the associated HIV AIDS infection. Topical therapy with clotrimazole troches, miconazole mucoadhesive tablets, or nystatin swish and swallow is recommended as initial therapy in HIV seronegative patients and in HIV seropositive patients with mild thrush. Patients with recurrent infection, moderate to severe illness, or immunosuppression (CD4 <100 cells/microL) should be treated with systemic fluconazole ( an initial 200 mg loading dose, followed by 100 to 200 mg daily for up to 14 after clinical improvement).

Actinic cheilitis – A variety of treatments are used for the management of actinic cheilitis depending upon its severity. Simple observation with regular visits or treatment with liquid nitrogen is advised in case of focal mild or moderate actinic cheilitis. Patients with multifocal or diffuse symptoms may benefit from first-line therapy with topical medications (eg, topical fluorouracil, imiquimod). 5% fluorouracil cream is applied locally twice a day for two to four weeks. Discomfort associated with fluorouracil may lead to poor compliance and patient may be switched to imiquimod 5% cream ( three times per week for four to six weeks). Some may also require photodynamic or laser therapy. Patients with severe diffuse actinic cheilitis without evidence of high-grade dysplasia or cancer on biopsy should be treated with laser ablation with carbon dioxide (CO2) laser or erbium:yttrium-aluminum-garnet (Er: YAG). Surgical excision (vermilionectomy) ensures the histopathologic examination of the entire vermilion and is the treatment of choice for actinic cheilitis with high-grade dysplasia on biopsy.

Drug-induced cheilitis – Lip moisturizers, emollients, and cessation of offending drugs lead to complete resolution of symptoms.

Glandular cheilitis and cheilitis granulomatosis – Various therapies have been implicated for glandular cheilitis, including systemic antibiotics and corticosteroids (topical, intralesional, or systemic), and vermilionectomy (in case of severe symptoms).

Surgery

In severe cases, the affected tissues may need to be removed. Advanced options include:

  • laser ablation, where a laser removes the outer layers of sun-damaged skin
  • cryotherapy, where the affected patches of skin are frozen off
  • vermilionectomy, where the outer layer of the lip is surgically removed
  • electrocautery, where an electrical current is used to remove the abnormal patch

Cosmetic fillers, which are applied by injection, can help with droopy lips that cause angular cheilitis. It is also necessary to ensure that dentures fit properly.

Prevention

Avoiding excessive or long-term unprotected sun exposure is the best way to prevent actinic cheilitis.

Sun protection tips for the lips include

  • applying sunscreen to the body and face daily, even if not spending a long time outside
  • applying lip balms or moisturizers that contain sunscreen, frequently throughout the day, especially when in the sun
  • wearing a wide-brimmed hat and light, long-sleeved clothing in the sun
  • growing a beard or mustache in the case of men

Other ways to reduce the risk of developing actinic cheilitis include

  • stopping smoking or chewing tobacco
  • avoiding excessive alcohol use
  • avoiding tanning beds
  • avoiding creams, facial washes, and medications that thin the skin
  • using extra caution in the sun when on immunosuppressing or anti-inflammatory medications
  • treating cases of oncogenic human papillomavirus or the wart virus properly
  • keeping hydrated, especially when in the sun

References

Cheilitis – Causes, Symptoms, Diagnosis, Treatment

Cheilitis is an inflammation of the lips, which could be acute or chronic. The inflammation primarily arises in the vermilion zone but may extend to surrounding skin and less commonly, to the oral mucosa. It may be caused by a multitude of factors, including contact irritants or allergens, chronic sun exposure, and nutritional deficiencies, as well as by various cutaneous and systemic illnesses.

Cheilitis is inflammation of the lips. This inflammation may include the perioral skin (the skin around the mouth), the vermilion border, or the labial mucosa. The skin and the vermilion border are more commonly involved, as the mucosa is less affected by inflammatory and allergic reactions.[rx]

Types of Cheilitis

It is a general term, and there are many recognized types and different causes. Cheilitis can be either acute or chronic. Most cheilitis is caused by exogenous factors such as dryness (chapping) and acute sun exposure.[rx] Patch testing may identify allergens that cause cheilitis.[rx]

The lips can be inflamed because of an infection or skin condition

  • Herpes simplex
  • Angular cheilitis
  • Granulomatous cheilitis
  • Orofacial granulomatosis
  • Crohn skin disease
  • Actinic cheilitis
  • Exfoliative cheilitis
  • Glandular cheilitis
  • Lichenoid cheilitis
  • Cutaneous lupus erythematosus

They may be inflamed because of an allergytoxin, medication or injury.

  • Eczematous cheilitis
  • Allergic contact cheilitis
  • Pigmented contact cheilitis
  • Cheilitis in musicians
  • Contact reactions to lipsticks and other lip care products
  • Irritant contact dermatitis
  • Allergic contact dermatitis
  • Smoking and its effects on the skin
  • Sunburn
  • Isotretinoin treatment
  • Acitretin treatment
  • Denture stomatitis

Eczematous cheilitis most common form of cheilitis and is more prevalent in people with a history of allergies. 

  • Angular cheilitis/infective cheilitis – may present at any age with an equal male to female ratio but is especially likely in older individuals wearing dentures. Children suffering from these forms have a history of recurrent infections or immune defects.
  • Actinic cheilitis – is more prevalent in geographic areas with high ultraviolet (UV) irradiation, and in fair-skinned men who work outdoors (e.g., fishermen, farmers) in their fourth to the eighth decade of life. Certain genetic conditions associated with increased susceptibility to solar damage may predispose individuals to acquire actinic cheilitis at an early age (e.g., xeroderma pigmentosum, oculocutaneous albinism).
  • Glandular cheilitis – is a rare form of cheilitis, more prevalent in older males, but individuals in younger age and women also may be affected. The cause is unknown, but several factors have been identified, including atopy, infection, chronic exposure to the sun, repeated licking, and use of tobacco.
  • Cheilitis granulomatosis –  is rare. It primarily affects young adults but can occur at any age, with equal ration in male to female. It is idiopathic. However, there are several predisposing factors, including food allergy, genetics, infection, and atopy.

Causes of Cheilitis

  • Eczematous cheilitis –  could be a result of exogenous factors (irritant contact cheilitis, allergic cheilitis) or endogenous factors (atopic cheilitis).
  • Dry, chapped lips – Frequent exposure to hot or dry winds can cause loss of plasticity of keratin in vermillion, leading to sores and dry, scaly lips. The patient might get into the habit of chronic licking of lips to pick upscales, which further aggravates the problem. It is also referred to as irritant contact cheilitis.
  • Allergic Contact Cheilitis – A delayed-type hypersensitivity reaction to allergens that come in contact with the lips can cause inflammation of the lips. It is also known as lipstick cheilitis since several ingredients found in lipsticks may act as irritants. The most common cosmetic sensitizers identified by patch testing include fragrances, Myroxylon pereirae, and nickel. However, some ingredients unique to lipsticks may also cause lip dermatitis. For example, castor oil, colophony, shellac, azo dyes, sesame oil, preservatives, ozonated olive oil, propolis, and copolymers. Apart from lipsticks, allergic contact cheilitis can be caused by a variety of other substances that come into contact with lips. They could be found in mouthwashes, toothpaste, and even food. Lipstick cheilitis may present as persistent irritation and scaling, sometimes associated with edema and vascularization, confined to vermillion or extending beyond in some cases. Cheilitis caused by food may involve the skin around the mouth.
  • Atopic Cheilitis – Patients with a history of atopy or atopic dermatitis commonly have associated atopic cheilitis. It presents with dryness, erythema, scaling, and fissuring of lips.
  • Angular Cheilitis – Angular cheilitis, also known as angular stomatitis or perlèche, is an acute or chronic inflammation of the skin and adjacent labial mucosa at the angles of the mouth. It manifests as a roughly triangular area of erythema and edema at one, or more frequently both, angles of the mouth. The most common cause of angular cheilitis in adults is a fungal infection, Candida albicans, and less commonly, Staphylococcus aureus. Poor oral hygiene, ill-fitting dentures, or absence of teeth as in the elderly can lead to excessive moisture and maceration from saliva leading to these infections. Less commonly, the nutritional deficiencies, particularly those of riboflavin (B2), niacin (B3), pyridoxine (B6), folate (B9), iron, and general protein malnutrition, may produce smooth, shiny, red lips associated with angular stomatitis, collectively known as cheilosis. 
  • Infective cheilitis – Viral cheilitis: It is mainly due to the herpes simplex virus, especially type 1. The primary herpes infection (herpetic gingivostomatitis) combines post-vesicular erosive and crusted cheilitis with diffuse stomatitis leading to dysphagia, perioral vesicles, fever, and cervical lymphadenopathy. Recurrence of oral herpes affects the lips in most cases. It manifests as a cluster of blisters accompanied by a burning sensation. Next, the vesicles erode to leave behind crusted erosions that resolve in a week.
  • Bacterial Cheilitis – The most common cause of bacterial cheilitis is infection with group A Streptococcus or Staphylococcus.
  • Mycotic cheilitis  Cheilitis caused by candida manifests with erythema and painful edema of the lips, sometimes with fissures, and it is usually accompanied by acute (pseudomembranous candidiasis) or chronic stomatitis, and/or angular cheilitis. The diagnosis is confirmed by taking a specimen for mycological examination.
  • Parasitic cheilitis Leishmaniasis is a possible cause of cheilitis in endemic regions. It gives the appearance of an erythematous papule or plaque that gradually enlarges and then ulcerates or a permanent lip enlargement (macrocheilia).
  • Actinic Cheilitis – Actinic Cheilitis (also known as solar keratosis of the lip or actinic keratosis) originates from the proliferation of atypical epidermal keratinocytes due to chronic sun exposure. It is a premalignant condition and occasionally progresses to squamous cell carcinoma. Most cases are observed in outdoor workers, fair-skinned individuals, and during the fourth to eighth decades of life. The lower lip border receives the highest ultraviolet radiation, being at the right angle to the midday sun rays and poorly protected by melanocytes. Clinical symptoms are varied, depending upon the stage of the disease, and may include erythema, edema, plaques, and nodules and later develop into ulceration as the lesion becomes malignant. Notably, the lesions have a characteristic “sandpapery” feel to touch.
  • Drug-induced cheilitis – Systemic retinoids such as etretinate and isotretinoin cause dryness, erythema, scaling, and cracking of the lips (may include angles of the mouth) in almost all the patients. Less frequently, it may also be caused by any other drugs that cause dryness of mouth and lip.
  • Glandular cheilitis – It is a rare, chronic inflammation with tumefaction and sometimes suppuration of salivary glands at the lower lip. The most common clinical form is the simple cheilitis glandularis, which manifests as a moderate thickening of the lower lip with inflammatory dilated gland duct orifices, from which mucous saliva can be squeezed easily. Older males are most commonly affected, but can also be seen in young individuals and women. In the more severe suppurative form (Volkmann’s cheilitis), the lip is enlarged considerably and persistently (macrocheilia) and is associated with pain and tenderness. Crusts and scales cover the surface, beneath which the salivary duct openings may be found. Eventually, it results in a deep-seated infection that may cause the formation of abscess and fistulous tracts.
  • Cheilitis granulomatosis – Cheilitis granulomatosis is a persistent, idiopathic, nontender granulomatous inflammation of one or both lips. The initial manifestation is sudden diffuse or nodular swellings involving the upper lip, the lower lip, and one or both cheeks in decreasing incidence. Early attacks cause edema of lips that usually subsides in days to hours; however, recurrent attacks may lead to a persistent increase in swelling, leading to firm, rubber-like consistency of lips. Cheilitis granulomatosis can be isolated, idiopathic (Miescher cheilitis granulomatosis), or associated with various systemic conditions (sarcoidosis, Crohn’s disease, tuberculosis). The complete form of Melkersson Rosenthal syndrome combines cheilitis granulomatosis, peripheral facial paralysis, and a fissured tongue with loss of taste sensation.

Listed below are some of the known causes of actinic cheilitis and risk factors for the condition

  • Chronic sun exposure – The more often the lips are exposed to sunlight, the more likely damage is to occur.
  • Severe sunburn – Sunburn further damages skin cells and causes them to divide and regenerate, increasing the chances of cellular mutations.
  • Sex – Three times more men than women develop actinic cheilitis.
  • Fair skin – A majority of those with actinic cheilitis are white or fair-skinned. Rates are very high in people with albinism or those with skin pigment disorders.
  • Tropical, subtropical, or desert environments – Regions near the equator have increased ultraviolet exposure. Tropical and desert regions also typically have more sunny, warm days that encourage being outdoors.
  • Jobs that involve being outdoors – Jobs or hobbies that require being outdoors in the sun for more time increase the risk of sun damage. Lifeguards, construction workers, hikers, marathon runners, farmers, and sailors may have a higher chance of developing actinic cheilitis.
  • Age – Usually the result of chronic or long-term sun damage, the condition mostly impacts adults.
  • Smoking – Smoking or chewing tobacco can weaken lip epithelium and make it more vulnerable to sun damage.
  • Actinic prurigo – This rare, itchy photosensitivity condition causes the skin to be more sensitive to sun damage.
  • Excessive alcohol use.
  • Oncogenic human papillomavirus – the virus that causes warts.
  • Immune disorders or immunosuppressing medications – Medications that weaken and suppress the immune system usually increase the risk of sun damage.
  • Everted lower lip – When the lip is turned more outward instead of inward.

Symptoms of Cheilitis

The main things you’ll notice are irritation and soreness in the corner(s) of your mouth. One or both corners may be:

  • Bleeding
  • Blistered
  • Cracked
  • Crusty
  • Itchy
  • Painful
  • Red
  • Scaly
  • Swollen

Your lips can feel dry and uncomfortable. Sometimes your lips and mouth can feel like they’re burning. You also might have a bad taste in your mouth.

Other symptoms include:

  • bad taste in your mouth
  • burning feeling on your lips or mouth
  • lips feeling dry or chapped
  • difficulty eating as a result of the irritation

Diagnosis of Cheilitis

History and Physical Exam

  • Your physician would take you through a number of questions which might include the history of the onset of the problem, and any underlying or associated complaints or symptoms. The history would include questions about denture history, oral care, other chronic skin conditions, medicine or drug history, the habit of smoking, nutrition and diet, bowel movements, and acid reflux

Evaluation

The diagnosis of most cheilitis is based on clinical signs and a careful anamnesis.

  • The diagnosis of allergic contact cheilitis – is confirmed by a history of allergy and a relevant patch test reaction. Patients with negative patch testing are diagnosed with irritant contact cheilitis or atopic cheilitis.
  • A biopsy is required in cheilitis granulomatosa to confirm the diagnosis. Once the diagnosis of granulomatous cheilitis is made, a thorough etiological assessment is necessary.
  • A biopsy – is also important in chronic actinic cheilitis if there is suspicion of malignant transformation.
    Finally, in the case of allergic cheilitis, an allergy survey is required. It includes a careful history and appropriate allergy tests.
  • Physical Examination – A thorough examination by your physician will help narrow the diagnosis.
  • Lab Investigations – Oral swabs and biopsies help to rule the underlying cause of the disease and confirm the diagnosis. Oral swabs, also known as culture swabs, are done to rule out the infection from candida, staphylococcus bacteria or herpes simplex. A biopsy can help to diagnose a condition a lichen planus or a precancerous lesion.

Treatment of Cheilitis

The therapeutic management of cheilitis is symptomatic and etiological

The goal is to clear out the infection and keep the area dry so your skin isn’t infected again. Your doctor will recommend an antifungal cream to treat fungal infections. Some are:

  • nystatin (Mycostatin)
  • ketoconazole (Extina)
  • clotrimazole (Lotrimin)
  • miconazole (Lotrimin AF, Micatin, Monistat Derm)

If your infection is bacterial, your doctor will prescribe an antibacterial medication, such as:

  • mupirocin (Bactroban)
  • fusidic acid (Fucidin, Fucithalmic)

For someone with uncontrolled diabetes, treatment might include diet and lifestyle changes, insulin therapy, or diabetes medications. Vitamin supplements or changes in diet can help people who develop angular cheilitis due to poor nutrition.

Antibiotics

When the area is infected, then the underlying infection requires treatment. It is important to diagnose the cause of the infection since yeast infections, for example, will not respond to antibiotics. In most cases, a doctor can tell by looking at it whether the infection is bacterial or due to yeast.

Hygiene

Keeping the area clean and dry can ease pain and prevent an infection from worsening. A lip balm or protectant can relieve dryness and protect the skin from saliva. A doctor may also recommend a topical steroid cream, which can be applied to the skin to stimulate healing. A steroid cream may also help with pain and itching.

Fillers and injections

When an issue with the lip or mouth shape makes angular cheilitis more likely, or if a person has had several infections with angular cheilitis, a doctor might recommend treatment to change the shape of the mouth.

Dry, chapped lips – Avoidance of lip sucking, lip balms, or any other causative agent, and the local application of petroleum jelly is helpful.

Allergic contact cheilitis and atopic cheilitis – Excluding the allergen responsible and applying a low to medium intensity topical steroid and emollients. Sometimes a potent steroid (fludrocortisone) or off-label use of topical calcineurin inhibitors may be required.

Angular cheilitis – The treatment is maintaining oral hygiene, using dentures with the proper fit, using barrier creams (eg, zinc oxide paste) or petrolatum and treatment of sicca symptoms. Vitamin supplements could be given in case of nutritional deficiency. In case of cheilitis due to dentures, dentures must be removed before going to bed at night, brushed intensely, and then soaked in a solution of chlorhexidine gluconate or a dilute solution of bleach (10 drops of solution in a denture cup filled with water).

Infective cheilitis – Maintaining proper oral hygiene, and treatment of the underlying cause of infection is indicated. The most common infection is by Candida albicans which has different treatment approaches depending upon the associated HIV AIDS infection. Topical therapy with clotrimazole troches, miconazole mucoadhesive tablets, or nystatin swish and swallow is recommended as initial therapy in HIV seronegative patients and in HIV seropositive patients with mild thrush. Patients with recurrent infection, moderate to severe illness, or immunosuppression (CD4 <100 cells/microL) should be treated with systemic fluconazole ( an initial 200 mg loading dose, followed by 100 to 200 mg daily for up to 14 after clinical improvement).

Actinic cheilitis – A variety of treatments are used for the management of actinic cheilitis depending upon its severity. Simple observation with regular visits or treatment with liquid nitrogen is advised in case of focal mild or moderate actinic cheilitis. Patients with multifocal or diffuse symptoms may benefit from first-line therapy with topical medications (eg, topical fluorouracil, imiquimod). 5% fluorouracil cream is applied locally twice a day for two to four weeks. Discomfort associated with fluorouracil may lead to poor compliance and patient may be switched to imiquimod 5% cream ( three times per week for four to six weeks). Some may also require photodynamic or laser therapy. Patients with severe diffuse actinic cheilitis without evidence of high-grade dysplasia or cancer on biopsy should be treated with laser ablation with carbon dioxide (CO2) laser or erbium:yttrium-aluminum-garnet (Er: YAG). Surgical excision (vermilionectomy) ensures the histopathologic examination of the entire vermilion and is the treatment of choice for actinic cheilitis with high-grade dysplasia on biopsy.

Drug-induced cheilitis – Lip moisturizers, emollients, and cessation of offending drugs lead to complete resolution of symptoms.

Glandular cheilitis and cheilitis granulomatosis – Various therapies have been implicated for glandular cheilitis, including systemic antibiotics and corticosteroids (topical, intralesional, or systemic), and vermilionectomy (in case of severe symptoms).

Surgery

In severe cases, the affected tissues may need to be removed. Advanced options include:

  • laser ablation, where a laser removes the outer layers of sun-damaged skin
  • cryotherapy, where the affected patches of skin are frozen off
  • vermilionectomy, where the outer layer of the lip is surgically removed
  • electrocautery, where an electrical current is used to remove the abnormal patch

Cosmetic fillers, which are applied by injection, can help with droopy lips that cause angular cheilitis. It is also necessary to ensure that dentures fit properly.

Prevention

Avoiding excessive or long-term unprotected sun exposure is the best way to prevent actinic cheilitis.

Sun protection tips for the lips include

  • applying sunscreen to the body and face daily, even if not spending a long time outside
  • applying lip balms or moisturizers that contain sunscreen, frequently throughout the day, especially when in the sun
  • wearing a wide-brimmed hat and light, long-sleeved clothing in the sun
  • growing a beard or mustache in the case of men

Other ways to reduce the risk of developing actinic cheilitis include

  • stopping smoking or chewing tobacco
  • avoiding excessive alcohol use
  • avoiding tanning beds
  • avoiding creams, facial washes, and medications that thin the skin
  • using extra caution in the sun when on immunosuppressing or anti-inflammatory medications
  • treating cases of oncogenic human papillomavirus or the wart virus properly
  • keeping hydrated, especially when in the sun

References

Pediatric Granulomatous Arthritis; Symptoms, Treatment

Pediatric Granulomatous Arthritis/Blau syndrome (BS) is a rare autosomal dominant, autoinflammatory syndrome characterized by the clinical triad of granulomatous recurrent uveitis, dermatitis, and symmetric arthritis. The gene responsible for BS has been identified in the caspase recruitment domain gene CARD15/NOD2. In the majority of patients, the disease is characterized by early-onset, usually before 3-4years of age. The manifestations at disease onset are usually represented by articular and cutaneous involvement signs, generally followed later by ocular manifestations which are often the most relevant morbidity of BS.

Blau Syndrome is an autosomal dominant genetic inflammatory disorder which affects the skin, eyes, and joints. It is caused by a mutation in the NOD2 (CARD15) gene. Symptoms usually begin before the age of 4, and the disease manifests as early-onset cutaneous sarcoidosis, granulomatous arthritis, and uveitis.

Blau syndrome which is also known as familial or pediatric granulomatous arthritis or early-onset sarcoidosis (EOS), is a granulomatous disease with an autosomal dominant inheritance pattern. The typical sites that are affected are skin, including a maculopapular skin rash, joints, with polyarticular granulomatous arthritis, and eyes, with granulomatous uveitis. In severe cases, the granulomatous inflammation can disseminate to liver, lung and kidney. Diagnosis is made by a combination of medical history, histologic evidence of (non-caseating) granulomas at the site of inflammation and genetic testing for mutations in the NOD2/CARD15 gene.

Other Names

Arthrocutaneouveal granulomatosis; ACUG; Granulomatosis, familial, Blau type; Granulomatous inflammatory arthritis, dermatitis, and uveitis, familial; Synovitis granulomatous with uveitis and cranial neuropathies; Granulomatosis, familial juvenile systemic; Jabs Syndrome, Early Onset Sarcoidosis
Familial Juvenile Systemic Disease

Pathophysiology

The NOD2 protein is part of the NOD family of proteins. These proteins form intracellular pattern recognition molecules that recognize danger signals such as toxins, bacteria or viruses and are an important part of innate immunity. NOD2 specifically recognizes muramyl dipeptide that is part of the bacterial cell wall peptidoglycan. When activated NOD2 leads to NF-kappa beta release, which in turn promotes apoptosis.

NOD2 mutations in Blau syndrome affect the nucleotide-binding domain of the protein. This leads to a gain of function that is now independent of muramyl dipeptide concentration, resulting in excessive NF kappa beta activation. Interestingly, susceptibility to Crohn’s disease has also been associated with mutations in NOD2, which shares some phenotypic similarities with Blau such as multisystem granulomatous inflammation. Polymorphisms associated with Crohn’s effect a different region of the NOD2 gene.

Recently, Mycobacterium avium ss. paratuberculosis (MAP) DNA has been identified in affected tissues from Blau patients. This organism has been implicated in the pathogenesis of Crohn’s and has also been found in patients with sarcoidosis. It is possible that NOD2 mutations in Blau could allow the persistence of MAP, leading to aberrant inflammation.

Causes of Blau Syndrome

The elucidation that the gene defect in BS involves the CARD15/NOD2 gene has stimulated many investigators, to define how this gene operates as part of the innate immune system, that responds to bacterial polysaccharides, such as muramyl dipeptide, to induce signaling pathways that induce cytokine responses and protect the organism. In BS the genetic defect seems to lead to overexpression, and poor control of the inflammatory response leading to widespread granulomatous, inflammation and tissue damage.[rx][rx]

Pediatric Granulomatous Arthritis

Symptoms of Blau Syndrome

  • Arthritis typically affects peripheral joints mainly wrists, knees, ankles, and proximal interphalangeal (PIP) joints of the hands.
  • Tenosynovitis is equally a characteristic feature; tendon sheaths appear enlarged on examination; most often the extensor tendons of the wrist, the pes anserinus, peroneal and flexor tibialis tendon sheaths are affected.
  • Lymphocyte subpopulations, microcytic anemia (HB = 8.2 g/dl; MCV = 59.4 fl),
  • Anisocytosis and anisochromia on the manual blood smear, a slightly elevated level of C-reactive protein (9.28 mg/l), the lowered concentration of iron without other iron irregularities,
  • Deficiency of class M and G3 immunoglobulins, and vitamin D3 deficiency.
  • Symmetrical knee and ankle arthritis without erosive and destructive changes in the joints.
  • Tenosynovitis and synovitis were excluded.
  • Eczematous dermatitis decreased,
  • Multiple subcutaneous nodules emerged on both upper and lower limbs, as well as on the torso;
  • The skin lesions responded well to the escalation of the glucocorticoid dose.
  • Recurrent diarrhea and concomitant abdominal pain
  • Features included fever, sialadenitis,
  • Lymphadenopathy,
  • Erythema nodosum,
  • Leukocytoclastic vasculitis,
  • Transient neuropathies,
  • Granulomatous glomerular and interstitial nephritis, interstitial lung disease,
  • Arterial hypertension, pericarditis,
  • Pulmonary embolism,
  • Hepatic granulomas, splenic involvement, and chronic renal failure.

Cutaneous findings

  • Dermatitis in the form of a dark red, slightly scaly, maculopapular, or eczematoid-like or lichenoid-like rash may occur frequently in the first year of life.[rx ,rx]
  • Dermatitis is often symmetric, on the trunk and/or extremities and is usually intermittent with spontaneous resolution,
  • Other described cutaneous findings are represented by erythema nodosum, leukocytoclastic vasculitis, bilateral leg ulcers, ichthyosis Vulgaris and pityriasis lichenoides.[rx] ,[rx], [rx]

Ocular findings

  • Granulomatous uveitis is a frequent manifestation (70–80%), often bilateral and with a chronic recurrent course.[rx ,rx]
  • Ocular granulomatosis is often referred to as the blurred vision, painful and red eyes, floaters and photophobia. [rx]
  • Ocular involvement can potentially evolve into moderate or severe visual loss, thus representing in many patients the most severe manifestation of these diseases.[rx ,rx]

Uveitis

  • It can also affect all the ocular segments, with iridocyclitis, band keratopathy with inflammatory precipitates and vitrinite.[rx ,rx]
  • Involvement of the posterior ocular segment with chorioretinitis, vasculitis, macular oedema with retinal detachment, and optic neuritis has been described in several cases.[rx]
  • Cataracts, inflammatory glaucoma, peripheral synechiae, increased intraocular pressure and optic atrophy can represent uveitis complications.[rx]


[stextbox id=’custom’]

Comparative analysis of patient’s phenotype with the phenotype of patients with BS carrying germline NOD2 mutations
Clinical manifestation Somatic p.Arg334Gln Patients with BS with germline NOD2mutations
p.Arg334Gln All patients
n 1 7 15
Age at disease onset (mo), median (IQR) 36 20 (14.5-23) 20 (11.5-24)
Skin rash, n (%) 1 (100) 7 (100) 13 (86.7)
Articular manifestations, n (%)
 Patients with joint disease 1 (100) 7 (100) 14 (93.3)
 Age at onset of articular disease (mo), median (IQR) 120 24 (20-27) 21.5 (13.5-28.5)
 Ratio polyarthritis/oligoarthritis (%) 0/100 57.1/42.9 71.4/28.6
 Joints affected Only large joints Both large and small joints Both large and small joints
 Chronic arthritis 1 (100) 7 (100) 14 (100)
 Tenosynovitis No 7 (100) 13 (92.8)
 Deformities No 4 (57.1) 6 (42.8)
Ocular manifestations, n (%)
 Patients with bilateral uveitis 1 (100) 6 (85.7) 11 (73.3)
 Panuveitis 1 (100) 5 (71.4) 8 (53.3)
Fever, n (%) No 3 (42.9) 7 (20)
Other manifestations, n (%)
 Cranial neuropathies No 1 (14.3) 1 (6.6)
 Headache No 2 (28.6) 3 (20)
 Renal involvement No 2 (28.6) 2 (13.3)
 Heart involvement No 1 (14.3) 1 (6.6)
 Pericarditis No No 1 (6.6)
 Hepatosplenomegaly No 1 (14.3) 2 (13.3)
 Adenopathies 1 (100) 1 (14.3) 2 (13.3)
 Oral ulcers No 1 (14.3) 2 (13.3)

IQR, Interquartile range.

[/stextbox]

Diagnosis of Blau Syndrome

On physical examination,

  • Numerous 1- to 2-mm, red-brown to pinkish-tan, flat-topped papules covered much of the face, trunk, and extremities. Individual lesions were closely grouped in oval clusters and linear arrays, with the confluence on the face.
  • The upper part of the chest knees, elbows, palms, and soles was relatively spared. No oral mucosal or conjunctival lesions were evident. No joint tenderness or swelling, lymphadenopathy, or hepatosplenomegaly was found.

The following laboratory tests produced normal results

  • Complete blood cell count – chemistry panel, serum calcium level, hepatic function panel, erythrocyte sedimentation rate, and urinalysis.
  • Blood test blood tests are important to exclude other diseases that can be associated with granulomatous inflammation (such as immune deficiency or Crohn’s disease). They are also important to see the extent of the inflammation and to evaluate the involvement of other organs (such as the kidney or liver).
  • The serum angiotensin-converting enzyme – level was 159 U/L (reference range, 13-100 U/L). A tuberculin skin test result was negative
  • Chest radiography results – were normal, and ultrasonography of the wrists, elbows, and knees revealed no synovial thickening or effusions.
  • Abdominal ultrasound scan (USS) – documented enlargement of the liver (30 mm below the right costal arch) and spleen (length 118 mm, with age-specific reference range up to 95 mm), with normal echogenicity of both organs.
  • Peripheral lymph node USS – revealed the presence of suspicious (hypoechogenic, up to 20 mm in diameter, without a marked sinus) supraclavicular, infraclavicular and axillary lymph nodes.
  • Histopathological examination – of one of the left supraclavicular lymph nodes showed reactive changes with neutrophilic infiltration.
  • Examination of the skin biopsy specimen demonstrated the presence of multiple granulomas composed of giant cells and epithelial cells at the border of the skin and subcutaneous tissue, raising suspicion of sarcoidosis or erythema annulare.
  • Clinical suspicion – It is relevant to consider Blau syndrome when a child presents a combination of symptoms (joint, skin, eye) out of the typical clinical triad. A detailed investigation into the family history should be considered because this disease is very rare and inherited in an autosomal dominant manner.
  • Demonstration of granulomas –  to make the diagnosis of Blau syndrome/EOS, the presence of typical granulomas in the affected tissue is essential. Granulomas can be seen on a biopsy of a skin lesion or of an inflamed joint. Other causes of granulomatous inflammation (such as tuberculosis, immune deficiency or other inflammatory diseases such as some vasculitides) need to be excluded by thorough clinical examination and blood tests, imaging, and other tests.
  • Genetic analysis – in the last couple of years, it has been possible to perform a genetic analysis of patients to ascertain the presence of mutations that are thought to be responsible for the development of Blau syndrome/EOS.
  • Advanced Skin biopsy – a skin biopsy involves the removal of a tiny piece of tissue from the skin and it is very easy to perform. If the skin biopsy shows granulomas, the diagnosis of Blau syndrome is made after the exclusion of all other diseases that are associated with granuloma formation.
  • The Genetic Testing Registry (GTR) – provides information about the genetic tests for this condition. The intended audience for the GTR is health care providers and researchers. Patients and consumers with specific questions about a genetic test should contact a health care provider or a genetics professional.
  • Genetic test – the only test that unambiguously confirms the diagnosis of Blau syndrome is a genetic test that shows the presence of a mutation in the NOD2 gene.

Treatment of Blau Syndrome

Treatment options should be guided by which organs are affected. Empiric experience has guided therapeutic choices as there have been no clinical trials owing to the rarity of Blau syndrome.

  • Consider no treatment as a rash may spontaneously resolve.
  • Superpotent (Class 1) or potent (class 2) topical corticosteroids may aid resolution of rash, although relapse may occur when discontinuing treatment.
  • Azithromycin (orally) 10mg/kg 3 times weekly was described as efficacious in one case report.

Arthritis and Occular Manifestations

  • NSAIDs may help with low-level joint inflammation.
  • Low-dose systemic corticosteroids (0.5mg/kg per day) with occasional up-titration of dose for flares has been the mainstay of treatment described historically.
  • Methotrexate has been used as a steroid-sparing agent.
  • Thalidomide at an initial dose of 2mg/kg has been used successfully in two children with refractory ocular disease.
  • Infliximab (5mg/kg IV infusion every 6 to 8 weeks) has been used in refractory cases.
  • Anakinra (100mg s.c.) once daily has been used in one patient with success, although another report of two patients showed no improvement.

Therapy

  • High-dose corticosteroids – have been shown to be efficacious when administered in concomitance with BS and EOS acute flares, as well as low-dose corticosteroids that are generally used during the quiescent stage.[rx ,rx]
  • Concomitant use of immunosuppressants – (methotrexate, or azathioprine, or mycophenolate mofetil) has been shown to be effective.[rx ,rx ,rx]
  • Further, the anti-TNF-α agent –  adalimumab, in combination with corticosteroids and/or methotrexate, has recently been shown to induce remission in case of refractory arthrocutaneous, ocular and systemic involvement.[rx]
  • Treatment with another anti-TNF-α drug – infliximab, has led to successful outcomes, also as monotherapy.[rx ,rx,rx]
  • Cyclosporine – (3 mg/kg/day) and intravenous human immunoglobulins at a supplementation dose (0.4 g/kg/month) were added to the therapeutic protocol.
  • If local treatment fails – oral prednisolone alone or in combination with MTX, azathioprine and mycophenolate mofetil, can be introduced.
  • High-dose prednisolone – can be used during attacks and low dose in more stable periods (10). Also, TNF-α inhibitors, such as infliximab and adalimumab, are used in BS/EOS (10, 11). Interleukin (IL)-1β receptor antagonists, such as anakinra and canakinumab, have been used with variable clinical outcome.
  • In cases with severe uveitis – canakinumab may be useful. In our case infliximab in combination with MTX induced remission for 8 months. However, when the MTX dose was decreased, symptoms reoccurred. Adalimumab improved uveitis and arthritis, but not a cutaneous eruption.
  • Anecdotal evidence supports – the use of steroids immunomodulation with TNF-α inhibitors and possibly other immunomodulatory therapies, such as thalidomide, methotrexate, and anti-IL-1 therapy, in the treatment of Blau syndrome.


References

Pediatric Granulomatous Arthritis

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