Cutis

Delusions of parasitosis (DOP) is a disorder in which patients erroneously insist that they are infested with parasites. These patients have an unshakable belief that their problems are medical. They rarely present to a psychiatrist and are almost always resistant to psychiatric referral. Thus, this disorder proves to be difficult to treat. The classic patient with DOP is a middle-aged woman frustrated by unsuccessful attempts to discover the cause of her ailment that has been affecting her for months or years.1 She may complain of a crawling, biting, burrowing sensation (formication) on or under her skin. She may claim her symptoms originate from insects or other creatures that infest her, her home, or her work. She may actually see the crawling culprits and be able to describe them in detail. This delusion may impinge on her activities of daily living, but she is otherwise a functional well-adjusted person. Oftentimes she will bring in proof of infestation that, under close examination, are pieces of lint or other nonparasitic materials.1 Despite thorough examination and reassurance, the patient relentlessly believes she is infested. She will most likely refuse referral to a psychiatrist, the one clinician with the most experience treating delusional disorders. Thus, it is important for the general practitioner and other nonpsychiatric clinicians to be familiar with DOP and its management.

Medical Management
Medical or psychiatric treatment aimed at eliminating the delusion should be attempted only after rapport with the patient has been established. Koo and Pham2 stated: "The greatest challenge in the treatment of delusional patients is in obtaining their agreement to start treatment with an antipsychotic medication." Numerous case reports have been published in which the clinician was unable to successfully treat DOP because of a lack of patient confidence.3-5 We modified a suggested management strategy first described by Gould and Gragg6 and incorporated strategies from a lecture on promoting a trusting relationship with delusional patients presented by Koo7 at the University of Southern California Dermatology Grand Rounds to create the following management strategy for clinicians:

1. Listen to the patient's story. Give the patient a few minutes to narrate and then proceed with a battery of direct questions. Do not dwell on the patient's psychiatric history, which will encourage trust and allow you to control the dialogue.
2. Thoroughly examine the patient's skin and any evidence of infestation that they bring. This task may seem dishonest when you are convinced the patient is delusional; however, it is possible there is a true infestation. Even if he/she is not infested, developing a bond with the patient will allow you to suggest treatments that the patient may otherwise not accept.2
3. Perform a biopsy if the patient insists, which will show that you genuinely care about his/her problem. Allow the patient to pick the skin area he/she believes is the most involved, but insist that if the biopsy is negative, he/she should entertain the possibility that the ailment may not be due to a living organism.
4. Show concern for how the condition has affected the patient's life. This technique has been shown to have a positive effect on the establishment of a good physician-patient relationship. Furthermore, it can help you individualize a therapeutic strategy for the patient in a way that does not reinforce the delusion. For example, you may say, "We will work diligently to relieve the stress this problem has caused you."
5. Be empathetic, not sympathetic. Let the patient know that you understand how the condition has left him/her feeling isolated.

Be aware that rapport with the patient will not always develop immediately. It may take a few visits before the patient is comfortable enough to accept treatment suggestions. Clinicians are most concerned with discussions with the patient relating to the diagnosis and treatment. Most patients will not accept a psychiatric diagnosis for a condition that they are sure is somatic. The following statements made by clinicians have been used with success:

• "You have a very difficult problem, but I will study the specimens you have brought and will try to help you in any way that I can."6
• "I did not find any parasites today, but I am willing to examine any evidence that you bring me in the future."2
• "I noticed that you have been suffering with this problem and this is really bothering you day and night. Maybe I can offer you a medication that can help relieve some of this distress."2
• "This medication has been known to help others with the same problem."8
• "I would like to refer you to a specialist for this disorder."9 (The patient is not immediately told that the specialist is a psychiatrist, but this fact is not denied if asked.)
• "You may very well have had an infestation initially that was adequately treated, and the only sign now is the residual sensation you feel in your skin. Given the experience you have had, I can understand how you feel that parasites are still there. This is a situation that I have seen before, and the medication that I am going to prescribe is usually very helpful in getting rid of this last remaining discomfort."10

Treating the patient's anxiety should be seriously considered.6 Benzodiazepines such as diazepam and alprazolam are commonly used for short-term treatment of anxiety. These medications are fast acting and can be withdrawn after a few weeks. Consultation with a psychiatrist can be helpful for clinicians who are not familiar or comfortable with these drugs. Treating the symptomatic itching or burning sensation experienced by many patients also should be considered. Crotamiton cream is useful for pruritus and possibly eradicates some organisms. Topical or intramuscular corticosteroids may be useful to alleviate the itching sensation. Additionally, an antihistamine can be useful. Over-the-counter anti-itch medications also can be used.

Treating the Delusion
Until the 1950s, DOP was considered a nontreatable disease. In 1946, Wilson and Miller11 reported that beyond treating the patient for syphilis, if indicated, "there is nothing whatsoever the dermatologist can do for such a patient." While viable treatment options are now available, management remains a challenge for clinicians, especially nonpsychiatrists. A meta-analysis of 1223 case reports of DOP showed marked improvement in full remission rates from the prepsychopharmacologic era (before 1960) to the postpsychopharmacologic era (after 1960)(33.9% to 51.9%, respectively).12 Most cases of DOP need to be treated. There have been few reported cases of spontaneous remission of DOP.13,14 Most experts will agree that referral to a psychiatrist is beneficial. It is debatable if psychiatrists are the only clinicians equipped to handle these patients or if dermatologists may and should prescribe pimozide.15,16 Koblenzer17 stated: "If not treated by the dermatologist, [patients with DOP are] doomed to a prolonged, expensive, and frenetic search from doctor to doctor, to exterminator, to entomologist, and so on, without relief." Regardless of the medication used, the clinician must proceed with caution when suggesting treatment to patients with DOP. Commonly, when a clinician suggests psychiatric referral or medication, the patient responds angrily and does not return.5,18 Patients can become a danger to themselves and others. One man set fire to one of his apartments and flooded another19; other patients have committed suicide.13,20 It is important to note the extreme desperation in which these patients often find themselves. Many patients have tried relentlessly to find a treatment for their supposed infestation and often have found their clinician to be more of a hindrance than a help. One such case resulted in an attempt on the life of a family physician.21

Pimozide
Pimozide is approved by the US Food and Drug Administration for Tourette syndrome. It was first used in 1975 to treat somatic delusions, as reported in 5 patients.22 Since then, this neuroleptic agent has been considered the treatment of choice for DOP. Pimozide is a highly selective dopamine D2 blocker; thus, it is effective in treating psychoses. Pimozide also has some serotonin receptor blocking activity, which is theorized to contribute to its therapeutic effects. Other neurologic effects include blockade of a-adrenergic receptor sites, voltage-gated calcium channels, and opiate receptors. Pimozide has approximately 50% oral bioavailability and its action lasts 24 to 48 hours, allowing for once-daily dosing. It is metabolized in the liver and primarily excreted in the urine.23 The most common side effects of pimozide are extrapyramidal symptoms, including pseudoparkinsonism, akathisia, and dystonia. Pseudoparkinsonism may manifest as muscle and joint stiffness, while akathisia is indicated by restlessness. These effects have been demonstrated in patients treated with a pimozide dosage as low as 2 mg daily.24 Symptoms can be controlled by anticholinergic medications, such as oral benztropine mesylate 1 to 4 mg once or twice daily, as needed, or diphenhydramine hydrochloride 25 mg 4 times daily, as needed. Benztropine mesylate is preferred versus diphenhydramine hydrochloride because it is not sedating. An acute dystonic reaction (ie, muscle spasm) rarely occurs because of the low dose of neuroleptic prescribed; however, the acute reaction also responds to anticholinergic agents.16 To minimize the risk for side effects, initially prescribe pimozide 1 mg daily, titrating up by 1 mg every 5 to 7 days (maximum, 10 mg daily), as needed. Koo and Lee25 recommend using the lowest effective dose of pimozide for the shortest possible duration. Pimozide at high doses has cardiotoxic properties manifested by long QT intervals and arrhythmias. Pretreatment and posttreatment electrocardiograms are recommended for all patients receiving pimozide.26 Discontinue increasing the dose when the QT interval is more than 0.52 seconds in adults or when there is a QT interval increase of 25% or more above the patient's baseline.27 Furthermore, coadministration of other drugs that increase the QT interval should be avoided, including but not limited to chlorpromazine, gatifloxacin, mefloquine, moxifloxacin hydrochloride, other class Ia and III antiarrhythmic agents, quinidine, tacrolimus, thioridazine hydrochloride, and ziprasidone hydrochloride or mesylate.28 Pimozide is the most studied and reported drug used for DOP. Most data on pimozide have come from individual or group case reports, though 2 double-blind placebo-controlled trials have been conducted. Of the 189 patients reported to be treated with pimozide in 22 articles, 79% reported a positive response to pimozide, 17% reported no response, and the rest were lost to follow-up.8,13,24,26,29-46 Side effects reported with pimozide included insomnia, drowsiness, and depression.34,41 Extrapyramidal symptoms such as pseudoparkinsonism and akathisia were not uncommon but generally were easily controlled with anticholinergic agents.13,24,26,34,35,38,40,41,45 Two cases of lethargy were reported with pimozide doses of up to 6 to 24 mg daily.41 An acute dystonic reaction occurred in a patient receiving 8 mg daily.40 The mean dosage of pimozide used for best effect was 5 mg daily, as per the case series for which this information was available.8,13,24,26,29-46 Both single and split dosing were reported as successful methods. The median duration of treatment to best results was 3.5 weeks, with a range of 3 days to 6 months. For patients who were followed long-term (4–12 mo), 100% (n=17) maintained complete or near complete resolution of symptoms (near complete in 1 patient) while receiving maintenance doses of pimozide. Daily doses ranged from 2 to 4 mg. For patients followed long-term who eventually discontinued pimozide, 43% (34/79) had subsequent recurrence of their symptoms. Of those patients re-treated with pimozide, 100% (n=20) had complete resolution of symptoms.8,13,24,26,29-46 Zomer et al46 studied 33 patients with DOP. A total of 61.1% (11/18) of patients reported improvement or full recovery with pimozide compared with the 20% (3/15) not treated. At a mean follow-up of 5 years, none of the patients who had full remission (5/33 with DOP) needed maintenance therapy.46 Hamann and Avnstorp34 conducted a double-blind, placebo-controlled, crossover trial in which participants showed a significant response to pimozide compared with placebo (P

Delusions of parasitosis (DOP) is a disorder in which patients erroneously insist that they are infested with parasites. These patients have an unshakable belief that their problems are medical. They rarely present to a psychiatrist and are almost always resistant to psychiatric referral. Thus, this disorder proves to be difficult to treat. The classic patient with DOP is a middle-aged woman frustrated by unsuccessful attempts to discover the cause of her ailment that has been affecting her for months or years.1 She may complain of a crawling, biting, burrowing sensation (formication) on or under her skin. She may claim her symptoms originate from insects or other creatures that infest her, her home, or her work. She may actually see the crawling culprits and be able to describe them in detail. This delusion may impinge on her activities of daily living, but she is otherwise a functional well-adjusted person. Oftentimes she will bring in proof of infestation that, under close examination, are pieces of lint or other nonparasitic materials.1 Despite thorough examination and reassurance, the patient relentlessly believes she is infested. She will most likely refuse referral to a psychiatrist, the one clinician with the most experience treating delusional disorders. Thus, it is important for the general practitioner and other nonpsychiatric clinicians to be familiar with DOP and its management.

Medical Management
Medical or psychiatric treatment aimed at eliminating the delusion should be attempted only after rapport with the patient has been established. Koo and Pham2 stated: "The greatest challenge in the treatment of delusional patients is in obtaining their agreement to start treatment with an antipsychotic medication." Numerous case reports have been published in which the clinician was unable to successfully treat DOP because of a lack of patient confidence.3-5 We modified a suggested management strategy first described by Gould and Gragg6 and incorporated strategies from a lecture on promoting a trusting relationship with delusional patients presented by Koo7 at the University of Southern California Dermatology Grand Rounds to create the following management strategy for clinicians:

1. Listen to the patient's story. Give the patient a few minutes to narrate and then proceed with a battery of direct questions. Do not dwell on the patient's psychiatric history, which will encourage trust and allow you to control the dialogue.
2. Thoroughly examine the patient's skin and any evidence of infestation that they bring. This task may seem dishonest when you are convinced the patient is delusional; however, it is possible there is a true infestation. Even if he/she is not infested, developing a bond with the patient will allow you to suggest treatments that the patient may otherwise not accept.2
3. Perform a biopsy if the patient insists, which will show that you genuinely care about his/her problem. Allow the patient to pick the skin area he/she believes is the most involved, but insist that if the biopsy is negative, he/she should entertain the possibility that the ailment may not be due to a living organism.
4. Show concern for how the condition has affected the patient's life. This technique has been shown to have a positive effect on the establishment of a good physician-patient relationship. Furthermore, it can help you individualize a therapeutic strategy for the patient in a way that does not reinforce the delusion. For example, you may say, "We will work diligently to relieve the stress this problem has caused you."
5. Be empathetic, not sympathetic. Let the patient know that you understand how the condition has left him/her feeling isolated.

Be aware that rapport with the patient will not always develop immediately. It may take a few visits before the patient is comfortable enough to accept treatment suggestions. Clinicians are most concerned with discussions with the patient relating to the diagnosis and treatment. Most patients will not accept a psychiatric diagnosis for a condition that they are sure is somatic. The following statements made by clinicians have been used with success:

• "You have a very difficult problem, but I will study the specimens you have brought and will try to help you in any way that I can."6
• "I did not find any parasites today, but I am willing to examine any evidence that you bring me in the future."2
• "I noticed that you have been suffering with this problem and this is really bothering you day and night. Maybe I can offer you a medication that can help relieve some of this distress."2
• "This medication has been known to help others with the same problem."8
• "I would like to refer you to a specialist for this disorder."9 (The patient is not immediately told that the specialist is a psychiatrist, but this fact is not denied if asked.)
• "You may very well have had an infestation initially that was adequately treated, and the only sign now is the residual sensation you feel in your skin. Given the experience you have had, I can understand how you feel that parasites are still there. This is a situation that I have seen before, and the medication that I am going to prescribe is usually very helpful in getting rid of this last remaining discomfort."10

Treating the patient's anxiety should be seriously considered.6 Benzodiazepines such as diazepam and alprazolam are commonly used for short-term treatment of anxiety. These medications are fast acting and can be withdrawn after a few weeks. Consultation with a psychiatrist can be helpful for clinicians who are not familiar or comfortable with these drugs. Treating the symptomatic itching or burning sensation experienced by many patients also should be considered. Crotamiton cream is useful for pruritus and possibly eradicates some organisms. Topical or intramuscular corticosteroids may be useful to alleviate the itching sensation. Additionally, an antihistamine can be useful. Over-the-counter anti-itch medications also can be used.

Treating the Delusion
Until the 1950s, DOP was considered a nontreatable disease. In 1946, Wilson and Miller11 reported that beyond treating the patient for syphilis, if indicated, "there is nothing whatsoever the dermatologist can do for such a patient." While viable treatment options are now available, management remains a challenge for clinicians, especially nonpsychiatrists. A meta-analysis of 1223 case reports of DOP showed marked improvement in full remission rates from the prepsychopharmacologic era (before 1960) to the postpsychopharmacologic era (after 1960)(33.9% to 51.9%, respectively).12 Most cases of DOP need to be treated. There have been few reported cases of spontaneous remission of DOP.13,14 Most experts will agree that referral to a psychiatrist is beneficial. It is debatable if psychiatrists are the only clinicians equipped to handle these patients or if dermatologists may and should prescribe pimozide.15,16 Koblenzer17 stated: "If not treated by the dermatologist, [patients with DOP are] doomed to a prolonged, expensive, and frenetic search from doctor to doctor, to exterminator, to entomologist, and so on, without relief." Regardless of the medication used, the clinician must proceed with caution when suggesting treatment to patients with DOP. Commonly, when a clinician suggests psychiatric referral or medication, the patient responds angrily and does not return.5,18 Patients can become a danger to themselves and others. One man set fire to one of his apartments and flooded another19; other patients have committed suicide.13,20 It is important to note the extreme desperation in which these patients often find themselves. Many patients have tried relentlessly to find a treatment for their supposed infestation and often have found their clinician to be more of a hindrance than a help. One such case resulted in an attempt on the life of a family physician.21

Pimozide
Pimozide is approved by the US Food and Drug Administration for Tourette syndrome. It was first used in 1975 to treat somatic delusions, as reported in 5 patients.22 Since then, this neuroleptic agent has been considered the treatment of choice for DOP. Pimozide is a highly selective dopamine D2 blocker; thus, it is effective in treating psychoses. Pimozide also has some serotonin receptor blocking activity, which is theorized to contribute to its therapeutic effects. Other neurologic effects include blockade of a-adrenergic receptor sites, voltage-gated calcium channels, and opiate receptors. Pimozide has approximately 50% oral bioavailability and its action lasts 24 to 48 hours, allowing for once-daily dosing. It is metabolized in the liver and primarily excreted in the urine.23 The most common side effects of pimozide are extrapyramidal symptoms, including pseudoparkinsonism, akathisia, and dystonia. Pseudoparkinsonism may manifest as muscle and joint stiffness, while akathisia is indicated by restlessness. These effects have been demonstrated in patients treated with a pimozide dosage as low as 2 mg daily.24 Symptoms can be controlled by anticholinergic medications, such as oral benztropine mesylate 1 to 4 mg once or twice daily, as needed, or diphenhydramine hydrochloride 25 mg 4 times daily, as needed. Benztropine mesylate is preferred versus diphenhydramine hydrochloride because it is not sedating. An acute dystonic reaction (ie, muscle spasm) rarely occurs because of the low dose of neuroleptic prescribed; however, the acute reaction also responds to anticholinergic agents.16 To minimize the risk for side effects, initially prescribe pimozide 1 mg daily, titrating up by 1 mg every 5 to 7 days (maximum, 10 mg daily), as needed. Koo and Lee25 recommend using the lowest effective dose of pimozide for the shortest possible duration. Pimozide at high doses has cardiotoxic properties manifested by long QT intervals and arrhythmias. Pretreatment and posttreatment electrocardiograms are recommended for all patients receiving pimozide.26 Discontinue increasing the dose when the QT interval is more than 0.52 seconds in adults or when there is a QT interval increase of 25% or more above the patient's baseline.27 Furthermore, coadministration of other drugs that increase the QT interval should be avoided, including but not limited to chlorpromazine, gatifloxacin, mefloquine, moxifloxacin hydrochloride, other class Ia and III antiarrhythmic agents, quinidine, tacrolimus, thioridazine hydrochloride, and ziprasidone hydrochloride or mesylate.28 Pimozide is the most studied and reported drug used for DOP. Most data on pimozide have come from individual or group case reports, though 2 double-blind placebo-controlled trials have been conducted. Of the 189 patients reported to be treated with pimozide in 22 articles, 79% reported a positive response to pimozide, 17% reported no response, and the rest were lost to follow-up.8,13,24,26,29-46 Side effects reported with pimozide included insomnia, drowsiness, and depression.34,41 Extrapyramidal symptoms such as pseudoparkinsonism and akathisia were not uncommon but generally were easily controlled with anticholinergic agents.13,24,26,34,35,38,40,41,45 Two cases of lethargy were reported with pimozide doses of up to 6 to 24 mg daily.41 An acute dystonic reaction occurred in a patient receiving 8 mg daily.40 The mean dosage of pimozide used for best effect was 5 mg daily, as per the case series for which this information was available.8,13,24,26,29-46 Both single and split dosing were reported as successful methods. The median duration of treatment to best results was 3.5 weeks, with a range of 3 days to 6 months. For patients who were followed long-term (4–12 mo), 100% (n=17) maintained complete or near complete resolution of symptoms (near complete in 1 patient) while receiving maintenance doses of pimozide. Daily doses ranged from 2 to 4 mg. For patients followed long-term who eventually discontinued pimozide, 43% (34/79) had subsequent recurrence of their symptoms. Of those patients re-treated with pimozide, 100% (n=20) had complete resolution of symptoms.8,13,24,26,29-46 Zomer et al46 studied 33 patients with DOP. A total of 61.1% (11/18) of patients reported improvement or full recovery with pimozide compared with the 20% (3/15) not treated. At a mean follow-up of 5 years, none of the patients who had full remission (5/33 with DOP) needed maintenance therapy.46 Hamann and Avnstorp34 conducted a double-blind, placebo-controlled, crossover trial in which participants showed a significant response to pimozide compared with placebo (P

Delusions of parasitosis (DOP) is a disorder in which patients erroneously insist that they are infested with parasites. These patients have an unshakable belief that their problems are medical. They rarely present to a psychiatrist and are almost always resistant to psychiatric referral. Thus, this disorder proves to be difficult to treat. The classic patient with DOP is a middle-aged woman frustrated by unsuccessful attempts to discover the cause of her ailment that has been affecting her for months or years.1 She may complain of a crawling, biting, burrowing sensation (formication) on or under her skin. She may claim her symptoms originate from insects or other creatures that infest her, her home, or her work. She may actually see the crawling culprits and be able to describe them in detail. This delusion may impinge on her activities of daily living, but she is otherwise a functional well-adjusted person. Oftentimes she will bring in proof of infestation that, under close examination, are pieces of lint or other nonparasitic materials.1 Despite thorough examination and reassurance, the patient relentlessly believes she is infested. She will most likely refuse referral to a psychiatrist, the one clinician with the most experience treating delusional disorders. Thus, it is important for the general practitioner and other nonpsychiatric clinicians to be familiar with DOP and its management.

Medical Management
Medical or psychiatric treatment aimed at eliminating the delusion should be attempted only after rapport with the patient has been established. Koo and Pham2 stated: "The greatest challenge in the treatment of delusional patients is in obtaining their agreement to start treatment with an antipsychotic medication." Numerous case reports have been published in which the clinician was unable to successfully treat DOP because of a lack of patient confidence.3-5 We modified a suggested management strategy first described by Gould and Gragg6 and incorporated strategies from a lecture on promoting a trusting relationship with delusional patients presented by Koo7 at the University of Southern California Dermatology Grand Rounds to create the following management strategy for clinicians:

1. Listen to the patient's story. Give the patient a few minutes to narrate and then proceed with a battery of direct questions. Do not dwell on the patient's psychiatric history, which will encourage trust and allow you to control the dialogue.
2. Thoroughly examine the patient's skin and any evidence of infestation that they bring. This task may seem dishonest when you are convinced the patient is delusional; however, it is possible there is a true infestation. Even if he/she is not infested, developing a bond with the patient will allow you to suggest treatments that the patient may otherwise not accept.2
3. Perform a biopsy if the patient insists, which will show that you genuinely care about his/her problem. Allow the patient to pick the skin area he/she believes is the most involved, but insist that if the biopsy is negative, he/she should entertain the possibility that the ailment may not be due to a living organism.
4. Show concern for how the condition has affected the patient's life. This technique has been shown to have a positive effect on the establishment of a good physician-patient relationship. Furthermore, it can help you individualize a therapeutic strategy for the patient in a way that does not reinforce the delusion. For example, you may say, "We will work diligently to relieve the stress this problem has caused you."
5. Be empathetic, not sympathetic. Let the patient know that you understand how the condition has left him/her feeling isolated.

Be aware that rapport with the patient will not always develop immediately. It may take a few visits before the patient is comfortable enough to accept treatment suggestions. Clinicians are most concerned with discussions with the patient relating to the diagnosis and treatment. Most patients will not accept a psychiatric diagnosis for a condition that they are sure is somatic. The following statements made by clinicians have been used with success:

• "You have a very difficult problem, but I will study the specimens you have brought and will try to help you in any way that I can."6
• "I did not find any parasites today, but I am willing to examine any evidence that you bring me in the future."2
• "I noticed that you have been suffering with this problem and this is really bothering you day and night. Maybe I can offer you a medication that can help relieve some of this distress."2
• "This medication has been known to help others with the same problem."8
• "I would like to refer you to a specialist for this disorder."9 (The patient is not immediately told that the specialist is a psychiatrist, but this fact is not denied if asked.)
• "You may very well have had an infestation initially that was adequately treated, and the only sign now is the residual sensation you feel in your skin. Given the experience you have had, I can understand how you feel that parasites are still there. This is a situation that I have seen before, and the medication that I am going to prescribe is usually very helpful in getting rid of this last remaining discomfort."10

Treating the patient's anxiety should be seriously considered.6 Benzodiazepines such as diazepam and alprazolam are commonly used for short-term treatment of anxiety. These medications are fast acting and can be withdrawn after a few weeks. Consultation with a psychiatrist can be helpful for clinicians who are not familiar or comfortable with these drugs. Treating the symptomatic itching or burning sensation experienced by many patients also should be considered. Crotamiton cream is useful for pruritus and possibly eradicates some organisms. Topical or intramuscular corticosteroids may be useful to alleviate the itching sensation. Additionally, an antihistamine can be useful. Over-the-counter anti-itch medications also can be used.

Treating the Delusion
Until the 1950s, DOP was considered a nontreatable disease. In 1946, Wilson and Miller11 reported that beyond treating the patient for syphilis, if indicated, "there is nothing whatsoever the dermatologist can do for such a patient." While viable treatment options are now available, management remains a challenge for clinicians, especially nonpsychiatrists. A meta-analysis of 1223 case reports of DOP showed marked improvement in full remission rates from the prepsychopharmacologic era (before 1960) to the postpsychopharmacologic era (after 1960)(33.9% to 51.9%, respectively).12 Most cases of DOP need to be treated. There have been few reported cases of spontaneous remission of DOP.13,14 Most experts will agree that referral to a psychiatrist is beneficial. It is debatable if psychiatrists are the only clinicians equipped to handle these patients or if dermatologists may and should prescribe pimozide.15,16 Koblenzer17 stated: "If not treated by the dermatologist, [patients with DOP are] doomed to a prolonged, expensive, and frenetic search from doctor to doctor, to exterminator, to entomologist, and so on, without relief." Regardless of the medication used, the clinician must proceed with caution when suggesting treatment to patients with DOP. Commonly, when a clinician suggests psychiatric referral or medication, the patient responds angrily and does not return.5,18 Patients can become a danger to themselves and others. One man set fire to one of his apartments and flooded another19; other patients have committed suicide.13,20 It is important to note the extreme desperation in which these patients often find themselves. Many patients have tried relentlessly to find a treatment for their supposed infestation and often have found their clinician to be more of a hindrance than a help. One such case resulted in an attempt on the life of a family physician.21

Pimozide
Pimozide is approved by the US Food and Drug Administration for Tourette syndrome. It was first used in 1975 to treat somatic delusions, as reported in 5 patients.22 Since then, this neuroleptic agent has been considered the treatment of choice for DOP. Pimozide is a highly selective dopamine D2 blocker; thus, it is effective in treating psychoses. Pimozide also has some serotonin receptor blocking activity, which is theorized to contribute to its therapeutic effects. Other neurologic effects include blockade of a-adrenergic receptor sites, voltage-gated calcium channels, and opiate receptors. Pimozide has approximately 50% oral bioavailability and its action lasts 24 to 48 hours, allowing for once-daily dosing. It is metabolized in the liver and primarily excreted in the urine.23 The most common side effects of pimozide are extrapyramidal symptoms, including pseudoparkinsonism, akathisia, and dystonia. Pseudoparkinsonism may manifest as muscle and joint stiffness, while akathisia is indicated by restlessness. These effects have been demonstrated in patients treated with a pimozide dosage as low as 2 mg daily.24 Symptoms can be controlled by anticholinergic medications, such as oral benztropine mesylate 1 to 4 mg once or twice daily, as needed, or diphenhydramine hydrochloride 25 mg 4 times daily, as needed. Benztropine mesylate is preferred versus diphenhydramine hydrochloride because it is not sedating. An acute dystonic reaction (ie, muscle spasm) rarely occurs because of the low dose of neuroleptic prescribed; however, the acute reaction also responds to anticholinergic agents.16 To minimize the risk for side effects, initially prescribe pimozide 1 mg daily, titrating up by 1 mg every 5 to 7 days (maximum, 10 mg daily), as needed. Koo and Lee25 recommend using the lowest effective dose of pimozide for the shortest possible duration. Pimozide at high doses has cardiotoxic properties manifested by long QT intervals and arrhythmias. Pretreatment and posttreatment electrocardiograms are recommended for all patients receiving pimozide.26 Discontinue increasing the dose when the QT interval is more than 0.52 seconds in adults or when there is a QT interval increase of 25% or more above the patient's baseline.27 Furthermore, coadministration of other drugs that increase the QT interval should be avoided, including but not limited to chlorpromazine, gatifloxacin, mefloquine, moxifloxacin hydrochloride, other class Ia and III antiarrhythmic agents, quinidine, tacrolimus, thioridazine hydrochloride, and ziprasidone hydrochloride or mesylate.28 Pimozide is the most studied and reported drug used for DOP. Most data on pimozide have come from individual or group case reports, though 2 double-blind placebo-controlled trials have been conducted. Of the 189 patients reported to be treated with pimozide in 22 articles, 79% reported a positive response to pimozide, 17% reported no response, and the rest were lost to follow-up.8,13,24,26,29-46 Side effects reported with pimozide included insomnia, drowsiness, and depression.34,41 Extrapyramidal symptoms such as pseudoparkinsonism and akathisia were not uncommon but generally were easily controlled with anticholinergic agents.13,24,26,34,35,38,40,41,45 Two cases of lethargy were reported with pimozide doses of up to 6 to 24 mg daily.41 An acute dystonic reaction occurred in a patient receiving 8 mg daily.40 The mean dosage of pimozide used for best effect was 5 mg daily, as per the case series for which this information was available.8,13,24,26,29-46 Both single and split dosing were reported as successful methods. The median duration of treatment to best results was 3.5 weeks, with a range of 3 days to 6 months. For patients who were followed long-term (4–12 mo), 100% (n=17) maintained complete or near complete resolution of symptoms (near complete in 1 patient) while receiving maintenance doses of pimozide. Daily doses ranged from 2 to 4 mg. For patients followed long-term who eventually discontinued pimozide, 43% (34/79) had subsequent recurrence of their symptoms. Of those patients re-treated with pimozide, 100% (n=20) had complete resolution of symptoms.8,13,24,26,29-46 Zomer et al46 studied 33 patients with DOP. A total of 61.1% (11/18) of patients reported improvement or full recovery with pimozide compared with the 20% (3/15) not treated. At a mean follow-up of 5 years, none of the patients who had full remission (5/33 with DOP) needed maintenance therapy.46 Hamann and Avnstorp34 conducted a double-blind, placebo-controlled, crossover trial in which participants showed a significant response to pimozide compared with placebo (P

Muir-Torre syndrome (MTS) was first described by Muir et al1 in 1967 and Torre2 in 1968 as a disorder characterized by the association of sebaceous gland neoplasms and visceral malignancies, most commonly colon cancer. Diagnostic criteria for MTS are the synchronous or metachronous occurrence of at least one sebaceous gland neoplasm and at least one visceral malignancy.3,4 The sebaceous gland neoplasms include adenomas, carcinomas, and sebaceomas (sebaceous epitheliomas). The visceral malignancies are most commonly colorectal and genitourinary but can include a variety of other visceral cancers. Diagnosis of MTS also can be established if the patient has multiple keratoacanthomas with multiple visceral malignancies and a family history of MTS.5 It is a rare autosomal dominant genodermatosis of variable expressivity that is thought to result from a mutation in mismatch repair genes and associated microsatellite instability. Muir-Torre syndrome represents a genetic predisposition to visceral neoplasia and the diagnosis can be suggested based on a cutaneous finding. In some cases, the histopathologic findings of a sebaceous neoplasm may serve as the first clue to the diagnosis. Thus, the pathologist may play an important role in the initial diagnosis. According to Curry et al,6 more than 200 cases of MTS have been described since 1982. We report 2 patients with MTS; the pathologist first suggested the diagnosis in both patients.

Case Reports
Patient 1—A 52-year-old woman with a history of colon adenocarcinoma and multiple skin lesions presented to the dermatologist in 2006 for a lesion on the left lower eyelid. The lesion was excised and sent to pathology for evaluation. On microscopic examination, a well-differentiated sebaceous carcinoma was noted. Immunoperoxidase studies were performed. The stain for the mutS homolog 2, colon cancer, nonpolyposis type 1 (Escherichia coli) gene, MSH2, showed loss of expression in tumor cells. Expression of the mutL homolog 1, colon cancer, nonpolyposis type 2 (E coli) gene, MLH1, was intact. The patient's medical history included sebaceous hyperplasia of the left naris in 1993, and the right naris and right temple in 1994. In December 1995, at 41 years of age, the patient was diagnosed with Dukes C node-positive colon adenocarcinoma and underwent subtotal colectomy and subsequent adjuvant chemotherapy. In 1999, she had a sebaceous adenoma removed from her right forehead and a sebaceous lesion, with differential including sebaceous hyperplasia and adenoma, removed from her mid forehead. The patient underwent total hysterectomy and bilateral salpingo-oophorectomy in 2000 for leiomyomas. The patient's family history was equally complex. Her mother had a history of colon, gastric, uterine, and urethral cancer. Two brothers died from colon cancer, one at 16 and the other at 39 years of age. The patient's maternal grandfather, maternal uncle, and a maternal first cousin were all diagnosed with colon cancer. One maternal aunt was diagnosed with uterine cancer and another with ovarian cancer. One maternal cousin was diagnosed with both breast and colon cancer and another was diagnosed with renal cell carcinoma. Patient 2—A 55-year-old man presented in 2005 with an indurated, elevated, smooth, dome-shaped papule approximately 4 mm on the right supraclavicular region. Results of shave excision showed poorly differentiated sebaceous carcinoma. Immunoperoxidase stains were performed using antibodies directed against DNA mismatch repair proteins MLH1, MSH2, mutS homolog 6 (E coli) MSH6, and postmeiotic segregation PMS2. Neoplastic cells showed aberrant loss of MSH2 and MSH6 gene expression with retention of MLH1 and PMS2 gene expression. The patient had a medical history of moderately differentiated adenocarcinoma of the cecum at 35 years of age. A diagnosis of MTS was made. Since 2005, several sites of actinic keratoses, a moderately differentiated squamous cell carcinoma on the left cheek and right aspect of the neck, and a malignant melanoma in situ (superficial spreading type) on the right side of the flank were found and removed. In September 2006, the patient presented with concerns of worsening epigastric pain and belching. Endoscopic evaluation demonstrated a large ulcer in the fundus of stomach. A biopsy specimen of the ulcer showed poorly differentiated adenocarcinoma. The patient later died from complications of gastric surgery. The patient's family history included uterine and fallopian tube tumors in his mother. Several other relatives died from unknown cancers.

Comment
Muir-Torre syndrome is the association of at least one sebaceous gland neoplasm and at least one visceral malignancy (Table).3,5,7-10 Colonic polyps and keratoacanthomas also are frequent findings.3,4 We diagnosed both our patients with MTS based on their histories of colon adenocarcinomas in conjunction with sebaceous carcinomas. Genetic testing supported this diagnosis.

The most common visceral malignancies associated with MTS are colorectal, followed by genitourinary.3,4,7,11-15 Less frequently occurring cancers in MTS are breast carcinoma and hematologic disorders.11 A variety of other visceral cancers also have been reported. Unlike colorectal carcinoma in the general population, colorectal carcinoma in patients with MTS usually is proximal to or at the splenic flexure.4,16 In addition, on average, it occurs about a decade earlier in patients with MTS (median age, 50 years) than in the general population (age range, 55–65 years). Approximately 15% of women with MTS develop endometrial cancer.4 Upper gastrointestinal tract cancers, as seen in patient 2, are uncommon. A review of the literature revealed only 2 other reported cases of gastric carcinoma.17,18 There are 3 types of cutaneous neoplasms characteristic of MTS, including (1) sebaceous adenomas, (2) sebaceous carcinomas, and (3) sebaceomas. Sebaceous adenomas are composed of dermal sebaceous lobules with a peripheral layer of smaller basaloid cells.6 Cystic sebaceous adenoma and sebaceous adenoma with features of keratoacanthoma are considered highly specific markers of MTS.3,6,8 In fact, cystic sebaceous neoplasms have only been observed in patients with MTS to date.8,19 Sebaceous carcinomas are malignant neoplasms that demonstrate variable sebocytic differentiation, irregular architecture of the lobules, and cytologic features of malignancy (ie, pleomorphism, hyperchromatism, mitotic activity).16,20 Sebaceomas, sebaceous epitheliomas, and basal cell carcinomas with sebaceous differentiation are characterized by nests of basaloid cells randomly admixed with sebocytes. The small basaloid cells outnumber the mature sebocytes. There are scattered mitoses but no atypia.21 Investigators have suggested that any sebaceous neoplasm that is difficult to classify should be considered a marker for MTS.3,6,8,13 Sebaceous hyperplasia has not been associated with MTS; however, lesions of sebaceous gland hyperplasia with unusual features should lead to further investigation. Basal cell carcinomas and actinic keratoses rarely have been described in MTS.3 Keratoacanthoma alone may be associated with MTS, but if there is sebaceous differentiation histologically or if keratoacanthomas are present in multiplicity in an individual with a family history of visceral malignancy, they are deemed to be highly specific markers for MTS.6 Most sebaceous lesions in MTS occur in the head and neck region and a small proportion involve the eyelid. Sebaceous neoplasms usually are of low malignancy, with the exception of sebaceous carcinomas of the eyelid, which have been reported to metastasize in at least a few cases.7 Because they have almost no metastatic potential, sebaceous adenomas and epitheliomas can be treated with complete excision. However, sebaceous carcinomas, which constitute 30% of the sebaceous neoplasms in MTS,22 have an aggressive growth pattern and metastatic potential and should be treated with wide surgical excision or Mohs micrographic surgery, which nearly eliminates the chance of recurrence in extraocular locations. Unfortunately, lesions of the eyelid may have metastatic recurrence, even with adequate initial excision.4 Oral isotretinoin alone or in combination with interferon alfa may suppress the development of sebaceous neoplasms in MTS.3,12 Sebaceous gland neoplasms precede the visceral cancer diagnosis in 22% of patients, occur concurrently in 6% of patients, and appear after the visceral malignancy in 56% of patients.13 In some cases, the cutaneous findings may precede the appearance of the internal disease by as many as 25 years or follow the diagnosis of an initial cancer by as many as 37 years.4 The mean age for the appearance of skin tumors is 53 years and the detection of the initial visceral neoplasm usually is approximately 50 years.3,4 The disease is more common in men.3,4,14,15,19,23 Approximately 40% of patients with sebaceous neoplasms have one or more visceral malignancies.8,12,19 Therefore, all patients with a diagnosis of sebaceous neoplasm should undergo an evaluation for the presence of underlying visceral malignancies. The inheritance pattern of MTS is autosomal dominant with a high degree of penetrance and variable expression. Sporadic cases also are known to develop. Germ-line mutations of the DNA mismatch repair genes MSH2 and MLH1 in patients with MTS suggest it often represents a phenotypic variant of hereditary nonpolyposis colon cancer (HNPCC). Hereditary nonpolyposis colon cancer is an autosomal dominant predisposition to colorectal cancer and other malignancies that also are frequently associated with mutations of MSH2 and MLH1 genes. Accordingly, affected family members of patients with MTS may manifest characteristic HNPCC tumors with or without cutaneous tumors typical of MTS.24 In HNPCC, the proportion of MSH2 mutations is almost equivalent to the proportion of MLH1 mutations, but MTS is most frequently caused by germ-line mutations in MSH2.23-25 Recently, Singh et al26 noted that in the 94 cases of sebaceous neoplasms they examined, MSH2 and MSH6 status was the same. Thus, when one was intact, the other was intact, and when one was deficient, the other was deficient, which mirrors our findings in patient 2. No mutation is found in 25% of patients with HNPCC as well as in some cases of MTS.13,27 Once an inherited germ-line mutation in one allele of either DNA mismatch repair gene MSH2 or MLH1 occurs, a somatic loss-of-function alteration of the remaining wild-type allele results in a mismatch repair deficiency. The mismatch repair system normally repairs small errors in repeat sequences of the DNA (microsatellites), which occur during replication. Therefore, mismatch repair deficiency results in accumulating mutations of these microsatellites, which is termed microsatellite instability (Figure). Tumor tissue in both patients with HNPCC and MTS shows microsatellite instability.

Currently, the diagnosis of MTS is based on clinical criteria. Immunohistochemical staining for MSH2 and MLH1 is a practical initial approach to confirm the diagnosis of MTS. Once a sebaceous skin tumor is noted, the pathologist may perform immunohistochemical staining using antibodies against MSH2 and MLH1 proteins in skin tumor tissue as an initial screening for mismatch repair defects. This procedure is an efficient and cost-effective method of screening and has a high predictive value for the diagnosis of DNA mismatch repair–deficient MTS.22,25 If immunohistochemical staining shows loss of MSH2 or MLH1 protein expression, molecular genetic analysis could then be performed. Moreover, cancer surveillance as well as genetic testing and counseling for the patient and family members can be initiated. Cancers, including both sebaceous neoplasms and visceral malignancies, associated with MTS have a more indolent course than they would if unassociated with this syndrome, even after metastases develop.3,4 Because these low-grade malignancies tend to permit prolonged survival, even metastatic disease may respond well to aggressive surgical treatment. One of our patients (patient 1) remains cancer free 13 years after treatment of her node-positive colon adenocarcinoma, which may reflect the indolent course of visceral malignancies associated with MTS.

Conclusion
We recommend consideration of MTS in any patient who has sebaceous neoplasms, particularly because sebaceous gland neoplasms are rare and cutaneous lesions may be the first sign of the disease. Immunohistochemical stains for MSH2 and MLH1 protein expression in skin tumor tissue should be performed, and patients should have a complete evaluation for gastrointestinal or genitourinary cancers. Because this syndrome has an autosomal dominant inheritance pattern, genetic counseling should be offered to all family members. All relatives who inherit the DNA mismatch repair defect have a substantially increased risk for visceral malignancies and therefore should also undergo routine cancer surveillance. The identification of occult malignancies is especially important in these patients, as the tumors often are amenable to treatment, even in the presence of metastasis.

Muir-Torre syndrome (MTS) was first described by Muir et al1 in 1967 and Torre2 in 1968 as a disorder characterized by the association of sebaceous gland neoplasms and visceral malignancies, most commonly colon cancer. Diagnostic criteria for MTS are the synchronous or metachronous occurrence of at least one sebaceous gland neoplasm and at least one visceral malignancy.3,4 The sebaceous gland neoplasms include adenomas, carcinomas, and sebaceomas (sebaceous epitheliomas). The visceral malignancies are most commonly colorectal and genitourinary but can include a variety of other visceral cancers. Diagnosis of MTS also can be established if the patient has multiple keratoacanthomas with multiple visceral malignancies and a family history of MTS.5 It is a rare autosomal dominant genodermatosis of variable expressivity that is thought to result from a mutation in mismatch repair genes and associated microsatellite instability. Muir-Torre syndrome represents a genetic predisposition to visceral neoplasia and the diagnosis can be suggested based on a cutaneous finding. In some cases, the histopathologic findings of a sebaceous neoplasm may serve as the first clue to the diagnosis. Thus, the pathologist may play an important role in the initial diagnosis. According to Curry et al,6 more than 200 cases of MTS have been described since 1982. We report 2 patients with MTS; the pathologist first suggested the diagnosis in both patients.

Case Reports
Patient 1—A 52-year-old woman with a history of colon adenocarcinoma and multiple skin lesions presented to the dermatologist in 2006 for a lesion on the left lower eyelid. The lesion was excised and sent to pathology for evaluation. On microscopic examination, a well-differentiated sebaceous carcinoma was noted. Immunoperoxidase studies were performed. The stain for the mutS homolog 2, colon cancer, nonpolyposis type 1 (Escherichia coli) gene, MSH2, showed loss of expression in tumor cells. Expression of the mutL homolog 1, colon cancer, nonpolyposis type 2 (E coli) gene, MLH1, was intact. The patient's medical history included sebaceous hyperplasia of the left naris in 1993, and the right naris and right temple in 1994. In December 1995, at 41 years of age, the patient was diagnosed with Dukes C node-positive colon adenocarcinoma and underwent subtotal colectomy and subsequent adjuvant chemotherapy. In 1999, she had a sebaceous adenoma removed from her right forehead and a sebaceous lesion, with differential including sebaceous hyperplasia and adenoma, removed from her mid forehead. The patient underwent total hysterectomy and bilateral salpingo-oophorectomy in 2000 for leiomyomas. The patient's family history was equally complex. Her mother had a history of colon, gastric, uterine, and urethral cancer. Two brothers died from colon cancer, one at 16 and the other at 39 years of age. The patient's maternal grandfather, maternal uncle, and a maternal first cousin were all diagnosed with colon cancer. One maternal aunt was diagnosed with uterine cancer and another with ovarian cancer. One maternal cousin was diagnosed with both breast and colon cancer and another was diagnosed with renal cell carcinoma. Patient 2—A 55-year-old man presented in 2005 with an indurated, elevated, smooth, dome-shaped papule approximately 4 mm on the right supraclavicular region. Results of shave excision showed poorly differentiated sebaceous carcinoma. Immunoperoxidase stains were performed using antibodies directed against DNA mismatch repair proteins MLH1, MSH2, mutS homolog 6 (E coli) MSH6, and postmeiotic segregation PMS2. Neoplastic cells showed aberrant loss of MSH2 and MSH6 gene expression with retention of MLH1 and PMS2 gene expression. The patient had a medical history of moderately differentiated adenocarcinoma of the cecum at 35 years of age. A diagnosis of MTS was made. Since 2005, several sites of actinic keratoses, a moderately differentiated squamous cell carcinoma on the left cheek and right aspect of the neck, and a malignant melanoma in situ (superficial spreading type) on the right side of the flank were found and removed. In September 2006, the patient presented with concerns of worsening epigastric pain and belching. Endoscopic evaluation demonstrated a large ulcer in the fundus of stomach. A biopsy specimen of the ulcer showed poorly differentiated adenocarcinoma. The patient later died from complications of gastric surgery. The patient's family history included uterine and fallopian tube tumors in his mother. Several other relatives died from unknown cancers.

Comment
Muir-Torre syndrome is the association of at least one sebaceous gland neoplasm and at least one visceral malignancy (Table).3,5,7-10 Colonic polyps and keratoacanthomas also are frequent findings.3,4 We diagnosed both our patients with MTS based on their histories of colon adenocarcinomas in conjunction with sebaceous carcinomas. Genetic testing supported this diagnosis.

The most common visceral malignancies associated with MTS are colorectal, followed by genitourinary.3,4,7,11-15 Less frequently occurring cancers in MTS are breast carcinoma and hematologic disorders.11 A variety of other visceral cancers also have been reported. Unlike colorectal carcinoma in the general population, colorectal carcinoma in patients with MTS usually is proximal to or at the splenic flexure.4,16 In addition, on average, it occurs about a decade earlier in patients with MTS (median age, 50 years) than in the general population (age range, 55–65 years). Approximately 15% of women with MTS develop endometrial cancer.4 Upper gastrointestinal tract cancers, as seen in patient 2, are uncommon. A review of the literature revealed only 2 other reported cases of gastric carcinoma.17,18 There are 3 types of cutaneous neoplasms characteristic of MTS, including (1) sebaceous adenomas, (2) sebaceous carcinomas, and (3) sebaceomas. Sebaceous adenomas are composed of dermal sebaceous lobules with a peripheral layer of smaller basaloid cells.6 Cystic sebaceous adenoma and sebaceous adenoma with features of keratoacanthoma are considered highly specific markers of MTS.3,6,8 In fact, cystic sebaceous neoplasms have only been observed in patients with MTS to date.8,19 Sebaceous carcinomas are malignant neoplasms that demonstrate variable sebocytic differentiation, irregular architecture of the lobules, and cytologic features of malignancy (ie, pleomorphism, hyperchromatism, mitotic activity).16,20 Sebaceomas, sebaceous epitheliomas, and basal cell carcinomas with sebaceous differentiation are characterized by nests of basaloid cells randomly admixed with sebocytes. The small basaloid cells outnumber the mature sebocytes. There are scattered mitoses but no atypia.21 Investigators have suggested that any sebaceous neoplasm that is difficult to classify should be considered a marker for MTS.3,6,8,13 Sebaceous hyperplasia has not been associated with MTS; however, lesions of sebaceous gland hyperplasia with unusual features should lead to further investigation. Basal cell carcinomas and actinic keratoses rarely have been described in MTS.3 Keratoacanthoma alone may be associated with MTS, but if there is sebaceous differentiation histologically or if keratoacanthomas are present in multiplicity in an individual with a family history of visceral malignancy, they are deemed to be highly specific markers for MTS.6 Most sebaceous lesions in MTS occur in the head and neck region and a small proportion involve the eyelid. Sebaceous neoplasms usually are of low malignancy, with the exception of sebaceous carcinomas of the eyelid, which have been reported to metastasize in at least a few cases.7 Because they have almost no metastatic potential, sebaceous adenomas and epitheliomas can be treated with complete excision. However, sebaceous carcinomas, which constitute 30% of the sebaceous neoplasms in MTS,22 have an aggressive growth pattern and metastatic potential and should be treated with wide surgical excision or Mohs micrographic surgery, which nearly eliminates the chance of recurrence in extraocular locations. Unfortunately, lesions of the eyelid may have metastatic recurrence, even with adequate initial excision.4 Oral isotretinoin alone or in combination with interferon alfa may suppress the development of sebaceous neoplasms in MTS.3,12 Sebaceous gland neoplasms precede the visceral cancer diagnosis in 22% of patients, occur concurrently in 6% of patients, and appear after the visceral malignancy in 56% of patients.13 In some cases, the cutaneous findings may precede the appearance of the internal disease by as many as 25 years or follow the diagnosis of an initial cancer by as many as 37 years.4 The mean age for the appearance of skin tumors is 53 years and the detection of the initial visceral neoplasm usually is approximately 50 years.3,4 The disease is more common in men.3,4,14,15,19,23 Approximately 40% of patients with sebaceous neoplasms have one or more visceral malignancies.8,12,19 Therefore, all patients with a diagnosis of sebaceous neoplasm should undergo an evaluation for the presence of underlying visceral malignancies. The inheritance pattern of MTS is autosomal dominant with a high degree of penetrance and variable expression. Sporadic cases also are known to develop. Germ-line mutations of the DNA mismatch repair genes MSH2 and MLH1 in patients with MTS suggest it often represents a phenotypic variant of hereditary nonpolyposis colon cancer (HNPCC). Hereditary nonpolyposis colon cancer is an autosomal dominant predisposition to colorectal cancer and other malignancies that also are frequently associated with mutations of MSH2 and MLH1 genes. Accordingly, affected family members of patients with MTS may manifest characteristic HNPCC tumors with or without cutaneous tumors typical of MTS.24 In HNPCC, the proportion of MSH2 mutations is almost equivalent to the proportion of MLH1 mutations, but MTS is most frequently caused by germ-line mutations in MSH2.23-25 Recently, Singh et al26 noted that in the 94 cases of sebaceous neoplasms they examined, MSH2 and MSH6 status was the same. Thus, when one was intact, the other was intact, and when one was deficient, the other was deficient, which mirrors our findings in patient 2. No mutation is found in 25% of patients with HNPCC as well as in some cases of MTS.13,27 Once an inherited germ-line mutation in one allele of either DNA mismatch repair gene MSH2 or MLH1 occurs, a somatic loss-of-function alteration of the remaining wild-type allele results in a mismatch repair deficiency. The mismatch repair system normally repairs small errors in repeat sequences of the DNA (microsatellites), which occur during replication. Therefore, mismatch repair deficiency results in accumulating mutations of these microsatellites, which is termed microsatellite instability (Figure). Tumor tissue in both patients with HNPCC and MTS shows microsatellite instability.

Currently, the diagnosis of MTS is based on clinical criteria. Immunohistochemical staining for MSH2 and MLH1 is a practical initial approach to confirm the diagnosis of MTS. Once a sebaceous skin tumor is noted, the pathologist may perform immunohistochemical staining using antibodies against MSH2 and MLH1 proteins in skin tumor tissue as an initial screening for mismatch repair defects. This procedure is an efficient and cost-effective method of screening and has a high predictive value for the diagnosis of DNA mismatch repair–deficient MTS.22,25 If immunohistochemical staining shows loss of MSH2 or MLH1 protein expression, molecular genetic analysis could then be performed. Moreover, cancer surveillance as well as genetic testing and counseling for the patient and family members can be initiated. Cancers, including both sebaceous neoplasms and visceral malignancies, associated with MTS have a more indolent course than they would if unassociated with this syndrome, even after metastases develop.3,4 Because these low-grade malignancies tend to permit prolonged survival, even metastatic disease may respond well to aggressive surgical treatment. One of our patients (patient 1) remains cancer free 13 years after treatment of her node-positive colon adenocarcinoma, which may reflect the indolent course of visceral malignancies associated with MTS.

Conclusion
We recommend consideration of MTS in any patient who has sebaceous neoplasms, particularly because sebaceous gland neoplasms are rare and cutaneous lesions may be the first sign of the disease. Immunohistochemical stains for MSH2 and MLH1 protein expression in skin tumor tissue should be performed, and patients should have a complete evaluation for gastrointestinal or genitourinary cancers. Because this syndrome has an autosomal dominant inheritance pattern, genetic counseling should be offered to all family members. All relatives who inherit the DNA mismatch repair defect have a substantially increased risk for visceral malignancies and therefore should also undergo routine cancer surveillance. The identification of occult malignancies is especially important in these patients, as the tumors often are amenable to treatment, even in the presence of metastasis.

Muir-Torre syndrome (MTS) was first described by Muir et al1 in 1967 and Torre2 in 1968 as a disorder characterized by the association of sebaceous gland neoplasms and visceral malignancies, most commonly colon cancer. Diagnostic criteria for MTS are the synchronous or metachronous occurrence of at least one sebaceous gland neoplasm and at least one visceral malignancy.3,4 The sebaceous gland neoplasms include adenomas, carcinomas, and sebaceomas (sebaceous epitheliomas). The visceral malignancies are most commonly colorectal and genitourinary but can include a variety of other visceral cancers. Diagnosis of MTS also can be established if the patient has multiple keratoacanthomas with multiple visceral malignancies and a family history of MTS.5 It is a rare autosomal dominant genodermatosis of variable expressivity that is thought to result from a mutation in mismatch repair genes and associated microsatellite instability. Muir-Torre syndrome represents a genetic predisposition to visceral neoplasia and the diagnosis can be suggested based on a cutaneous finding. In some cases, the histopathologic findings of a sebaceous neoplasm may serve as the first clue to the diagnosis. Thus, the pathologist may play an important role in the initial diagnosis. According to Curry et al,6 more than 200 cases of MTS have been described since 1982. We report 2 patients with MTS; the pathologist first suggested the diagnosis in both patients.

Case Reports
Patient 1—A 52-year-old woman with a history of colon adenocarcinoma and multiple skin lesions presented to the dermatologist in 2006 for a lesion on the left lower eyelid. The lesion was excised and sent to pathology for evaluation. On microscopic examination, a well-differentiated sebaceous carcinoma was noted. Immunoperoxidase studies were performed. The stain for the mutS homolog 2, colon cancer, nonpolyposis type 1 (Escherichia coli) gene, MSH2, showed loss of expression in tumor cells. Expression of the mutL homolog 1, colon cancer, nonpolyposis type 2 (E coli) gene, MLH1, was intact. The patient's medical history included sebaceous hyperplasia of the left naris in 1993, and the right naris and right temple in 1994. In December 1995, at 41 years of age, the patient was diagnosed with Dukes C node-positive colon adenocarcinoma and underwent subtotal colectomy and subsequent adjuvant chemotherapy. In 1999, she had a sebaceous adenoma removed from her right forehead and a sebaceous lesion, with differential including sebaceous hyperplasia and adenoma, removed from her mid forehead. The patient underwent total hysterectomy and bilateral salpingo-oophorectomy in 2000 for leiomyomas. The patient's family history was equally complex. Her mother had a history of colon, gastric, uterine, and urethral cancer. Two brothers died from colon cancer, one at 16 and the other at 39 years of age. The patient's maternal grandfather, maternal uncle, and a maternal first cousin were all diagnosed with colon cancer. One maternal aunt was diagnosed with uterine cancer and another with ovarian cancer. One maternal cousin was diagnosed with both breast and colon cancer and another was diagnosed with renal cell carcinoma. Patient 2—A 55-year-old man presented in 2005 with an indurated, elevated, smooth, dome-shaped papule approximately 4 mm on the right supraclavicular region. Results of shave excision showed poorly differentiated sebaceous carcinoma. Immunoperoxidase stains were performed using antibodies directed against DNA mismatch repair proteins MLH1, MSH2, mutS homolog 6 (E coli) MSH6, and postmeiotic segregation PMS2. Neoplastic cells showed aberrant loss of MSH2 and MSH6 gene expression with retention of MLH1 and PMS2 gene expression. The patient had a medical history of moderately differentiated adenocarcinoma of the cecum at 35 years of age. A diagnosis of MTS was made. Since 2005, several sites of actinic keratoses, a moderately differentiated squamous cell carcinoma on the left cheek and right aspect of the neck, and a malignant melanoma in situ (superficial spreading type) on the right side of the flank were found and removed. In September 2006, the patient presented with concerns of worsening epigastric pain and belching. Endoscopic evaluation demonstrated a large ulcer in the fundus of stomach. A biopsy specimen of the ulcer showed poorly differentiated adenocarcinoma. The patient later died from complications of gastric surgery. The patient's family history included uterine and fallopian tube tumors in his mother. Several other relatives died from unknown cancers.

Comment
Muir-Torre syndrome is the association of at least one sebaceous gland neoplasm and at least one visceral malignancy (Table).3,5,7-10 Colonic polyps and keratoacanthomas also are frequent findings.3,4 We diagnosed both our patients with MTS based on their histories of colon adenocarcinomas in conjunction with sebaceous carcinomas. Genetic testing supported this diagnosis.

The most common visceral malignancies associated with MTS are colorectal, followed by genitourinary.3,4,7,11-15 Less frequently occurring cancers in MTS are breast carcinoma and hematologic disorders.11 A variety of other visceral cancers also have been reported. Unlike colorectal carcinoma in the general population, colorectal carcinoma in patients with MTS usually is proximal to or at the splenic flexure.4,16 In addition, on average, it occurs about a decade earlier in patients with MTS (median age, 50 years) than in the general population (age range, 55–65 years). Approximately 15% of women with MTS develop endometrial cancer.4 Upper gastrointestinal tract cancers, as seen in patient 2, are uncommon. A review of the literature revealed only 2 other reported cases of gastric carcinoma.17,18 There are 3 types of cutaneous neoplasms characteristic of MTS, including (1) sebaceous adenomas, (2) sebaceous carcinomas, and (3) sebaceomas. Sebaceous adenomas are composed of dermal sebaceous lobules with a peripheral layer of smaller basaloid cells.6 Cystic sebaceous adenoma and sebaceous adenoma with features of keratoacanthoma are considered highly specific markers of MTS.3,6,8 In fact, cystic sebaceous neoplasms have only been observed in patients with MTS to date.8,19 Sebaceous carcinomas are malignant neoplasms that demonstrate variable sebocytic differentiation, irregular architecture of the lobules, and cytologic features of malignancy (ie, pleomorphism, hyperchromatism, mitotic activity).16,20 Sebaceomas, sebaceous epitheliomas, and basal cell carcinomas with sebaceous differentiation are characterized by nests of basaloid cells randomly admixed with sebocytes. The small basaloid cells outnumber the mature sebocytes. There are scattered mitoses but no atypia.21 Investigators have suggested that any sebaceous neoplasm that is difficult to classify should be considered a marker for MTS.3,6,8,13 Sebaceous hyperplasia has not been associated with MTS; however, lesions of sebaceous gland hyperplasia with unusual features should lead to further investigation. Basal cell carcinomas and actinic keratoses rarely have been described in MTS.3 Keratoacanthoma alone may be associated with MTS, but if there is sebaceous differentiation histologically or if keratoacanthomas are present in multiplicity in an individual with a family history of visceral malignancy, they are deemed to be highly specific markers for MTS.6 Most sebaceous lesions in MTS occur in the head and neck region and a small proportion involve the eyelid. Sebaceous neoplasms usually are of low malignancy, with the exception of sebaceous carcinomas of the eyelid, which have been reported to metastasize in at least a few cases.7 Because they have almost no metastatic potential, sebaceous adenomas and epitheliomas can be treated with complete excision. However, sebaceous carcinomas, which constitute 30% of the sebaceous neoplasms in MTS,22 have an aggressive growth pattern and metastatic potential and should be treated with wide surgical excision or Mohs micrographic surgery, which nearly eliminates the chance of recurrence in extraocular locations. Unfortunately, lesions of the eyelid may have metastatic recurrence, even with adequate initial excision.4 Oral isotretinoin alone or in combination with interferon alfa may suppress the development of sebaceous neoplasms in MTS.3,12 Sebaceous gland neoplasms precede the visceral cancer diagnosis in 22% of patients, occur concurrently in 6% of patients, and appear after the visceral malignancy in 56% of patients.13 In some cases, the cutaneous findings may precede the appearance of the internal disease by as many as 25 years or follow the diagnosis of an initial cancer by as many as 37 years.4 The mean age for the appearance of skin tumors is 53 years and the detection of the initial visceral neoplasm usually is approximately 50 years.3,4 The disease is more common in men.3,4,14,15,19,23 Approximately 40% of patients with sebaceous neoplasms have one or more visceral malignancies.8,12,19 Therefore, all patients with a diagnosis of sebaceous neoplasm should undergo an evaluation for the presence of underlying visceral malignancies. The inheritance pattern of MTS is autosomal dominant with a high degree of penetrance and variable expression. Sporadic cases also are known to develop. Germ-line mutations of the DNA mismatch repair genes MSH2 and MLH1 in patients with MTS suggest it often represents a phenotypic variant of hereditary nonpolyposis colon cancer (HNPCC). Hereditary nonpolyposis colon cancer is an autosomal dominant predisposition to colorectal cancer and other malignancies that also are frequently associated with mutations of MSH2 and MLH1 genes. Accordingly, affected family members of patients with MTS may manifest characteristic HNPCC tumors with or without cutaneous tumors typical of MTS.24 In HNPCC, the proportion of MSH2 mutations is almost equivalent to the proportion of MLH1 mutations, but MTS is most frequently caused by germ-line mutations in MSH2.23-25 Recently, Singh et al26 noted that in the 94 cases of sebaceous neoplasms they examined, MSH2 and MSH6 status was the same. Thus, when one was intact, the other was intact, and when one was deficient, the other was deficient, which mirrors our findings in patient 2. No mutation is found in 25% of patients with HNPCC as well as in some cases of MTS.13,27 Once an inherited germ-line mutation in one allele of either DNA mismatch repair gene MSH2 or MLH1 occurs, a somatic loss-of-function alteration of the remaining wild-type allele results in a mismatch repair deficiency. The mismatch repair system normally repairs small errors in repeat sequences of the DNA (microsatellites), which occur during replication. Therefore, mismatch repair deficiency results in accumulating mutations of these microsatellites, which is termed microsatellite instability (Figure). Tumor tissue in both patients with HNPCC and MTS shows microsatellite instability.

Currently, the diagnosis of MTS is based on clinical criteria. Immunohistochemical staining for MSH2 and MLH1 is a practical initial approach to confirm the diagnosis of MTS. Once a sebaceous skin tumor is noted, the pathologist may perform immunohistochemical staining using antibodies against MSH2 and MLH1 proteins in skin tumor tissue as an initial screening for mismatch repair defects. This procedure is an efficient and cost-effective method of screening and has a high predictive value for the diagnosis of DNA mismatch repair–deficient MTS.22,25 If immunohistochemical staining shows loss of MSH2 or MLH1 protein expression, molecular genetic analysis could then be performed. Moreover, cancer surveillance as well as genetic testing and counseling for the patient and family members can be initiated. Cancers, including both sebaceous neoplasms and visceral malignancies, associated with MTS have a more indolent course than they would if unassociated with this syndrome, even after metastases develop.3,4 Because these low-grade malignancies tend to permit prolonged survival, even metastatic disease may respond well to aggressive surgical treatment. One of our patients (patient 1) remains cancer free 13 years after treatment of her node-positive colon adenocarcinoma, which may reflect the indolent course of visceral malignancies associated with MTS.

Conclusion
We recommend consideration of MTS in any patient who has sebaceous neoplasms, particularly because sebaceous gland neoplasms are rare and cutaneous lesions may be the first sign of the disease. Immunohistochemical stains for MSH2 and MLH1 protein expression in skin tumor tissue should be performed, and patients should have a complete evaluation for gastrointestinal or genitourinary cancers. Because this syndrome has an autosomal dominant inheritance pattern, genetic counseling should be offered to all family members. All relatives who inherit the DNA mismatch repair defect have a substantially increased risk for visceral malignancies and therefore should also undergo routine cancer surveillance. The identification of occult malignancies is especially important in these patients, as the tumors often are amenable to treatment, even in the presence of metastasis.