Status Report From the American Acne & Rosacea Society on Medical Management of Acne in Adult Women, Part 3: Oral Therapies

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Status Report From the American Acne & Rosacea Society on Medical Management of Acne in Adult Women, Part 3: Oral Therapies
Author(s)
James Q. Del Rosso, DO
Julie C. Harper, MD
Emmy M. Graber, MD, MBA
Diane Thiboutot, MD
Nanette B. Silverberg, MD
Lawrence F. Eichenfield, MD

Selection of oral agents for treatment of AV in adult women is dependent on multiple factors including the patient’s age, medication history, child-bearing potential, clinical presentation, and treatment preference following a discussion of the anticipated benefits versus potential risks.1,2 In patients with the mixed inflammatory and comedonal clinical pattern of AV, oral antibiotics can be used concurrently with topical therapies when moderate to severe inflammatory lesions are noted.3,4 However, many adult women who had AV as teenagers have already utilized oral antibiotic therapies in the past and often are interested in alternative options, express concerns regarding antibiotic resistance, report a history of antibiotic-associated yeast infections or other side effects, and/or encounter issues related to drug-drug interactions.3,5-8 Oral hormonal therapies such as combination oral contraceptives (COCs) or spironolactone often are utilized to treat adult women with AV, sometimes in combination with each other or other agents. Combination oral contraceptives appear to be especially effective in the management of the U-shaped clinical pattern or predominantly inflammatory, late-onset AV.1,5,9,10 Potential warnings, contraindications, adverse effects, and drug-drug interactions are important to keep in mind when considering the use of oral hormonal therapies.8-10 Oral isotretinoin, which should be prescribed with strict adherence to the iPLEDGE™ program (https://www.ipledgeprogram.com/), remains a viable option for cases of severe nodular AV and selected cases of refractory inflammatory AV, especially when scarring and/or marked psychosocial distress are noted.1,2,5,11 Although it is recognized that adult women with AV typically present with either a mixed inflammatory and comedonal or U-shaped clinical pattern predominantly involving the lower face and anterolateral neck, the available data do not adequately differentiate the relative responsiveness of these clinical patterns to specific therapeutic agents.

Combination Oral Contraceptives

Combination oral contraceptives are commonly used to treat AV in adult women, including those without and those with measurable androgen excess (eg, polycystic ovary syndrome [PCOS]). Combination oral contraceptives contain ethinyl estradiol and a progestational agent (eg, progestin); the latter varies in terms of its nonselective receptor interactions and the relative magnitude or absence of androgenic effects.10,12,13 Although some COCs are approved by the US Food and Drug Administration (FDA) for AV, there is little data available to determine the comparative efficacy among these and other COCs.10,14 When choosing a COC for treatment of AV, it is best to select an agent whose effectiveness is supported by evidence from clinical studies.10,15

Mechanisms of Action

The reported mechanisms of action for COCs include inhibition of ovarian androgen production and ovulation through gonadotropin suppression; upregulated synthesis of sex hormone–binding globulin, which decreases free testosterone levels through receptor binding; and inhibition of 5α-reductase (by some progestins), which reduces conversion of testosterone to dihydrotestosterone, the active derivative that induces androgenic effects at peripheral target tissues.10,13,16,17

Therapeutic Benefits

Use of COCs to treat AV in adult women who do not have measurable androgen excess is most rational in patients who also desire a method of contraception. Multiple monotherapy studies have demonstrated the efficacy of COCs in the treatment of AV on the face and trunk.4,10,12,15,17,18 It may take a minimum of 3 monthly cycles of use before acne lesion counts begin to appreciably decrease.12,15,19-21 Initiating COC therapy during menstruation ensures the absence of pregnancy. Combination oral contraceptives may be used with other topical and oral therapies for AV.2,3,9,10 Potential ancillary benefits of COCs include normalization of the menstrual cycle; reduced premenstrual dysphoric disorder symptoms; and reduced risk of endometrial cancer (approximately 50%), ovarian cancer (approximately 40%), and colorectal cancer.22-24

Risks and Contraindications

It is important to consider the potential risks associated with the use of COCs, especially in women with AV who are not seeking a method of contraception. Side effects of COCs can include nausea, breast tenderness, breakthrough bleeding, and weight gain.25,26 Potential adverse associations of COCs are described in the Table. The major potential vascular associations include venous thromboembolism, myocardial infarction, and cerebrovascular accident, all of which are influenced by concurrent factors such as a history of smoking, age (≥35 years), and hypertension.27-32 It is recommended that blood pressure be measured before initiating COC therapy as part of the general examination.33

The potential increase in breast cancer risk appears to be low, while the cervical cancer risk is reported to increase relative to the duration of use.34-37 This latter observation may be due to the greater likelihood of unprotected sex in women using a COC and exposure to multiple sexual partners in some cases, which may increase the likelihood of oncogenic human papillomavirus infection of the cervix. If a dermatologist elects to prescribe a COC to treat AV, it has been suggested that the patient also consult with her general practitioner or gynecologist to undergo pelvic and breast examinations and a Papanicolaou test.33 The recommendation for initial screening for cervical cancer is within 3 years of initiation of sexual intercourse or by 21 years of age, whichever is first.33,38,39

 

 

Combination oral contraceptives are not ideal for all adult women with AV. Absolute contraindications are pregnancy and history of thromboembolic, cardiac, or hepatic disease; in women aged 35 years and older who smoke, relative contraindications include hypertension, diabetes, migraines, breastfeeding, and current breast or liver cancer.33 In adult women with AV who have relative contra-indications but are likely to benefit from the use of a COC when other options are limited or not viable, consultation with a gynecologist is prudent. Other than rifamycin antibiotics (eg, rifampin) and griseofulvin, there is no definitive evidence that oral antibiotics (eg, tetracycline) or oral antifungal agents reduce the contraceptive efficacy of COCs, although cautions remain in print within some approved package inserts.8

Spironolactone

Available since 1957, spironolactone is an oral aldos-terone antagonist and potassium-sparing diuretic used to treat hypertension and congestive heart failure.9 Recognition of its antiandrogenic effects led to its use in dermatology to treat certain dermatologic disorders in women (eg, hirsutism, alopecia, AV).1,4,5,9,10 Spironolactone is not approved for AV by the FDA; therefore, available data from multiple independent studies and retrospective analyses that have been collectively reviewed support its efficacy when used as both monotherapy or in combination with other agents in adult women with AV, especially those with a U-shaped pattern and/or late-onset AV.9,40-43

Mechanism of Action

Spironolactone inhibits sebaceous gland activity through peripheral androgen receptor blockade, inhibition of 5α-reductase, decrease in androgen production, and increase in sex hormone–binding globulin.9,10,40

Therapeutic Benefits

Good to excellent improvement of AV in women, many of whom are postadolescent, has ranged from 66% to 100% in published reports9,40-43; however, inclusion and exclusion criteria, dosing regimens, and concomitant therapies were not usually controlled. Spironolactone has been used to treat AV in adult women as monotherapy or in combination with topical agents, oral antibiotics, and COCs.9,40-42 Additionally, dose-ranging studies have not been completed with spironolactone for AV.9,40 The suggested dose range is 50 mg to 200 mg daily; however, it usually is best to start at 50 mg daily and increase to 100 mg daily if clinical response is not adequate after 2 to 3 months. The gastrointestinal (GI) absorption of spironolactone is increased when ingested with a high-fat meal.9,10

Once effective control of AV is achieved, it is optimal to use the lowest dose needed to continue reasonable suppression of new AV lesions. There is no defined end point for spironolactone use in AV, with or without concurrent PCOS, as many adult women usually continue treatment with low-dose therapy because they experience marked flaring shortly after the drug is stopped.9

Risks and Contraindications

Side effects associated with spironolactone are dose related and include increased diuresis, migraines, menstrual irregularities, breast tenderness, gynecomastia, fatigue, and dizziness.9,10,40-44 Side effects (particularly menstrual irregularities and breast tenderness) are more common at doses higher than 100 mg daily, especially when used as monotherapy without concurrent use of a COC.9,40

Spironolactone-associated hyperkalemia is most clinically relevant in patients on higher doses (eg, 100–200 mg daily), in those with renal impairment and/or congestive heart failure, and when used concurrently with certain other medications. In any patient on spironolactone, the risk of clinically relevant hyperkalemia may be increased by coingestion of potassium supplements, potassium-based salt substitutes, potassium-sparing diuretics (eg, amiloride, triamterene); aldosterone antagonists and angiotensin-converting enzyme inhibitors (eg, lisinopril, benazepril); angiotensin II receptor blockers (eg, losartan, valsartan); and tri-methoprim (with or without sulfamethoxazole).8,9,40,45 Spironolactone may also increase serum levels of lithium or digoxin.9,40,45,46 For management of AV, it is best that spironolactone be avoided in patients taking any of these medications.9

In healthy adult women with AV who are not on medications or supplements that interact adversely with spironolactone, there is no definitive recommendation regarding monitoring of serum potassium levels during treatment with spironolactone, and it has been suggested that monitoring serum potassium levels in this subgroup is not necessary.47 However, each clinician is advised to choose whether or not they wish to obtain baseline and/or periodic serum potassium levels when prescribing spironolactone for AV based on their degree of comfort and the patient’s history. Baseline and periodic blood testing to evaluate serum electrolytes and renal function are reasonable, especially as adult women with AV are usually treated with spironolactone over a prolonged period of time.9

The FDA black box warning for spironolactone states that it is tumorigenic in chronic toxicity studies in rats and refers to exposures 25- to 100-fold higher than those administered to humans.9,48 Although continued vigilance is warranted, evaluation of large populations of women treated with spironolactone do not suggest an association with increased risk of breast cancer.49,50

 

 

Spironolactone is a category C drug and thus should be avoided during pregnancy, primarily due to animal data suggesting risks of hypospadias and feminization in male fetuses.9 Importantly, there is an absence of reports linking exposure during pregnancy with congenital defects in humans, including in 2 known cases of high-dose exposures for maternal Bartter syndrome.9

The active metabolite, canrenone, is known to be present in breast milk at 0.2% of the maternal daily dose, but breastfeeding is generally believed to be safe with spironolactone based on evidence to date.9

Oral Antibiotics

Oral antibiotic therapy may be used in combination with a topical regimen to treat AV in adult women, keeping in mind some important caveats.1-7 For instance, monotherapy with oral antibiotics should be avoided, and concomitant use of benzoyl peroxide is suggested to reduce emergence of antibiotic-resistant Propionibacterium acnes strains.3,4 A therapeutic exit plan also is suggested when prescribing oral antibiotics to limit treatment to 3 to 4 months, if possible, to help mitigate the emergence of antibiotic-resistant bacteria (eg, staphylococci and streptococci).3-5,51

Tetracyclines, especially doxycycline and minocycline, are the most commonly prescribed agents. Doxycycline use warrants patient education on measures to limit the risks of esophageal and GI side effects and phototoxicity; enteric-coated and small tablet formulations have been shown to reduce GI side effects, especially when administered with food.3,52-55 In addition to vestibular side effects and hyperpigmentation, minocycline may be associated with rare but potentially severe adverse reactions such as drug hypersensitivity syndrome, autoimmune hepatitis, and lupus-like syndrome, which are reported more commonly in women.5,52,54 Vestibular side effects have been shown to decrease with use of extended-release tablets with weight-based dosing.53

Oral Isotretinoin

Oral isotretinoin is well established as highly effective for treatment of severe, recalcitrant AV, including nodular acne on the face and trunk.4,56 Currently available oral isotretinoins are branded generic formulations based on the pharmacokinetic profile of the original brand (Accutane [Roche Pharmaceuticals]) and with the use of Lidose Technology (Absorica [Cipher Pharmaceuticals]), which substantially increases GI absorption of isotretinoin in the absence of ingestion with a high-calorie, high-fat meal.57 The short- and long-term efficacy, dosing regimens, safety considerations, and serious teratogenic risks for oral isotretinoin are well published.4,56-58 Importantly, oral isotretinoin must be prescribed with strict adherence to the federally mandated iPLEDGE risk management program.

Low-dose oral isotretinoin therapy (<0.5 mg/kg–1 mg/kg daily) administered over several months longer than conventional regimens (ie, 16–20 weeks) has been suggested with demonstrated efficacy.57 However, this approach is not optimal due to the lack of established sustained clearance of AV after discontinuation of therapy and the greater potential for exposure to isotretinoin during pregnancy. Recurrences of AV do occur after completion of isotretinoin therapy, especially if cumulative systemic exposure to the drug during the initial course of treatment was inadequate.56,57

Oral isotretinoin has been shown to be effective in AV in adult women with or without PCOS with 0.5 mg/kg to 1 mg/kg daily and a total cumulative exposure of 120 mg/kg to 150 mg/kg.59 In one study, the presence of PCOS and greater number of nodules at baseline were predictive of a higher risk of relapse during the second year posttreatment.59

Conclusion

All oral therapies that are used to treat AV in adult women warrant individual consideration of possible benefits versus risks. Careful attention to possible side effects, patient-related risk factors, and potential drug-drug interactions is important. End points of therapy are not well established, with the exception of oral isotretinoin therapy. Clinicians must use their judgment in each case along with obtaining feedback from patients regarding the selection of therapy after a discussion of the available options.

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Author and Disclosure Information

Dr. Del Rosso is from Touro University College of Osteopathic Medicine, Henderson, Nevada, and Las Vegas Dermatology, Nevada. Dr. Harper is in private practice, Birmingham, Alabama. Dr. Graber is in private practice, Boston, Massachusetts. Dr. Thiboutot is from Penn State University Medical Center, Hershey. Dr. Silverberg is from the Department of Dermatology, Mount Sinai St. Luke’s-Roosevelt and Beth Israel Medical Center of the Icahn School of Medicine at Mount Sinai, New York, New York. Dr. Eichenfield is from the University of California, San Diego School of Medicine and Rady Children’s Hospital, San Diego.

Dr. Del Rosso is an advisory board member, consultant, and/or speaker for Allergan, Inc; Aqua Pharmaceuticals; Bayer Health Care Pharmaceuticals; Dermira, Inc; Ferndale Laboratories, Inc; Galderma Laboratories, LP; Mimetica; Promius Pharma; Ranbaxy Laboratories Limited; Sebacia; Suneva Medical, Inc; Unilever; and Valeant Pharmaceuticals International, Inc. He also is a researcher for Allergan, Inc; Ranbaxy Laboratories Limited; Sebacia; and Suneva Medical, Inc. Drs. Harper, Graber, and Eichenfield report no conflict of interest. Dr. Thiboutot is a consultant for and has received research grants from Allergan, Inc, and Galderma Laboratories, LP. Dr. Silverberg has been an investigator for Allergan, Inc, as well as an advisory board member for Galderma Laboratories, LP, and Johnson & Johnson Consumer Inc.

This article is an educational initiative of the American Acne & Rosacea Society (AARS) intended to be a general guide to assist the clinician. The content has been developed solely by the authors. There was no input or contribution from industry or any outside agency related to this publication. The content was reviewed and approved by the authors and Board of Directors of the AARS.This article is the third of a 3-part series.

Correspondence: James Q. Del Rosso, DO (jqdelrosso@yahoo.com).

Issue
Cutis - 96(6)
Publications
Cutis
Clinical Guidelines Hub
MDedge Dermatology
Topics
Acne
Page Number
376-382
Legacy Keywords
acne vulgaris, oral contraception, women, antibiotics
Sections
Drug Therapy
Author(s)
James Q. Del Rosso, DO
Julie C. Harper, MD
Emmy M. Graber, MD, MBA
Diane Thiboutot, MD
Nanette B. Silverberg, MD
Lawrence F. Eichenfield, MD
Author(s)
James Q. Del Rosso, DO
Julie C. Harper, MD
Emmy M. Graber, MD, MBA
Diane Thiboutot, MD
Nanette B. Silverberg, MD
Lawrence F. Eichenfield, MD
Author and Disclosure Information

Dr. Del Rosso is from Touro University College of Osteopathic Medicine, Henderson, Nevada, and Las Vegas Dermatology, Nevada. Dr. Harper is in private practice, Birmingham, Alabama. Dr. Graber is in private practice, Boston, Massachusetts. Dr. Thiboutot is from Penn State University Medical Center, Hershey. Dr. Silverberg is from the Department of Dermatology, Mount Sinai St. Luke’s-Roosevelt and Beth Israel Medical Center of the Icahn School of Medicine at Mount Sinai, New York, New York. Dr. Eichenfield is from the University of California, San Diego School of Medicine and Rady Children’s Hospital, San Diego.

Dr. Del Rosso is an advisory board member, consultant, and/or speaker for Allergan, Inc; Aqua Pharmaceuticals; Bayer Health Care Pharmaceuticals; Dermira, Inc; Ferndale Laboratories, Inc; Galderma Laboratories, LP; Mimetica; Promius Pharma; Ranbaxy Laboratories Limited; Sebacia; Suneva Medical, Inc; Unilever; and Valeant Pharmaceuticals International, Inc. He also is a researcher for Allergan, Inc; Ranbaxy Laboratories Limited; Sebacia; and Suneva Medical, Inc. Drs. Harper, Graber, and Eichenfield report no conflict of interest. Dr. Thiboutot is a consultant for and has received research grants from Allergan, Inc, and Galderma Laboratories, LP. Dr. Silverberg has been an investigator for Allergan, Inc, as well as an advisory board member for Galderma Laboratories, LP, and Johnson & Johnson Consumer Inc.

This article is an educational initiative of the American Acne & Rosacea Society (AARS) intended to be a general guide to assist the clinician. The content has been developed solely by the authors. There was no input or contribution from industry or any outside agency related to this publication. The content was reviewed and approved by the authors and Board of Directors of the AARS.This article is the third of a 3-part series.

Correspondence: James Q. Del Rosso, DO (jqdelrosso@yahoo.com).

Author and Disclosure Information

Dr. Del Rosso is from Touro University College of Osteopathic Medicine, Henderson, Nevada, and Las Vegas Dermatology, Nevada. Dr. Harper is in private practice, Birmingham, Alabama. Dr. Graber is in private practice, Boston, Massachusetts. Dr. Thiboutot is from Penn State University Medical Center, Hershey. Dr. Silverberg is from the Department of Dermatology, Mount Sinai St. Luke’s-Roosevelt and Beth Israel Medical Center of the Icahn School of Medicine at Mount Sinai, New York, New York. Dr. Eichenfield is from the University of California, San Diego School of Medicine and Rady Children’s Hospital, San Diego.

Dr. Del Rosso is an advisory board member, consultant, and/or speaker for Allergan, Inc; Aqua Pharmaceuticals; Bayer Health Care Pharmaceuticals; Dermira, Inc; Ferndale Laboratories, Inc; Galderma Laboratories, LP; Mimetica; Promius Pharma; Ranbaxy Laboratories Limited; Sebacia; Suneva Medical, Inc; Unilever; and Valeant Pharmaceuticals International, Inc. He also is a researcher for Allergan, Inc; Ranbaxy Laboratories Limited; Sebacia; and Suneva Medical, Inc. Drs. Harper, Graber, and Eichenfield report no conflict of interest. Dr. Thiboutot is a consultant for and has received research grants from Allergan, Inc, and Galderma Laboratories, LP. Dr. Silverberg has been an investigator for Allergan, Inc, as well as an advisory board member for Galderma Laboratories, LP, and Johnson & Johnson Consumer Inc.

This article is an educational initiative of the American Acne & Rosacea Society (AARS) intended to be a general guide to assist the clinician. The content has been developed solely by the authors. There was no input or contribution from industry or any outside agency related to this publication. The content was reviewed and approved by the authors and Board of Directors of the AARS.This article is the third of a 3-part series.

Correspondence: James Q. Del Rosso, DO (jqdelrosso@yahoo.com).

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Related Articles
Status Report From the American Acne & Rosacea Society on Medical Management of Acne in Adult Women, Part 1: Overview, Clinical Characteristics, and Laboratory Evaluation
Status Report From the American Acne & Rosacea Society on Medical Management of Acne in Adult Women, Part 2: Topical Therapies

Selection of oral agents for treatment of AV in adult women is dependent on multiple factors including the patient’s age, medication history, child-bearing potential, clinical presentation, and treatment preference following a discussion of the anticipated benefits versus potential risks.1,2 In patients with the mixed inflammatory and comedonal clinical pattern of AV, oral antibiotics can be used concurrently with topical therapies when moderate to severe inflammatory lesions are noted.3,4 However, many adult women who had AV as teenagers have already utilized oral antibiotic therapies in the past and often are interested in alternative options, express concerns regarding antibiotic resistance, report a history of antibiotic-associated yeast infections or other side effects, and/or encounter issues related to drug-drug interactions.3,5-8 Oral hormonal therapies such as combination oral contraceptives (COCs) or spironolactone often are utilized to treat adult women with AV, sometimes in combination with each other or other agents. Combination oral contraceptives appear to be especially effective in the management of the U-shaped clinical pattern or predominantly inflammatory, late-onset AV.1,5,9,10 Potential warnings, contraindications, adverse effects, and drug-drug interactions are important to keep in mind when considering the use of oral hormonal therapies.8-10 Oral isotretinoin, which should be prescribed with strict adherence to the iPLEDGE™ program (https://www.ipledgeprogram.com/), remains a viable option for cases of severe nodular AV and selected cases of refractory inflammatory AV, especially when scarring and/or marked psychosocial distress are noted.1,2,5,11 Although it is recognized that adult women with AV typically present with either a mixed inflammatory and comedonal or U-shaped clinical pattern predominantly involving the lower face and anterolateral neck, the available data do not adequately differentiate the relative responsiveness of these clinical patterns to specific therapeutic agents.

Combination Oral Contraceptives

Combination oral contraceptives are commonly used to treat AV in adult women, including those without and those with measurable androgen excess (eg, polycystic ovary syndrome [PCOS]). Combination oral contraceptives contain ethinyl estradiol and a progestational agent (eg, progestin); the latter varies in terms of its nonselective receptor interactions and the relative magnitude or absence of androgenic effects.10,12,13 Although some COCs are approved by the US Food and Drug Administration (FDA) for AV, there is little data available to determine the comparative efficacy among these and other COCs.10,14 When choosing a COC for treatment of AV, it is best to select an agent whose effectiveness is supported by evidence from clinical studies.10,15

Mechanisms of Action

The reported mechanisms of action for COCs include inhibition of ovarian androgen production and ovulation through gonadotropin suppression; upregulated synthesis of sex hormone–binding globulin, which decreases free testosterone levels through receptor binding; and inhibition of 5α-reductase (by some progestins), which reduces conversion of testosterone to dihydrotestosterone, the active derivative that induces androgenic effects at peripheral target tissues.10,13,16,17

Therapeutic Benefits

Use of COCs to treat AV in adult women who do not have measurable androgen excess is most rational in patients who also desire a method of contraception. Multiple monotherapy studies have demonstrated the efficacy of COCs in the treatment of AV on the face and trunk.4,10,12,15,17,18 It may take a minimum of 3 monthly cycles of use before acne lesion counts begin to appreciably decrease.12,15,19-21 Initiating COC therapy during menstruation ensures the absence of pregnancy. Combination oral contraceptives may be used with other topical and oral therapies for AV.2,3,9,10 Potential ancillary benefits of COCs include normalization of the menstrual cycle; reduced premenstrual dysphoric disorder symptoms; and reduced risk of endometrial cancer (approximately 50%), ovarian cancer (approximately 40%), and colorectal cancer.22-24

Risks and Contraindications

It is important to consider the potential risks associated with the use of COCs, especially in women with AV who are not seeking a method of contraception. Side effects of COCs can include nausea, breast tenderness, breakthrough bleeding, and weight gain.25,26 Potential adverse associations of COCs are described in the Table. The major potential vascular associations include venous thromboembolism, myocardial infarction, and cerebrovascular accident, all of which are influenced by concurrent factors such as a history of smoking, age (≥35 years), and hypertension.27-32 It is recommended that blood pressure be measured before initiating COC therapy as part of the general examination.33

The potential increase in breast cancer risk appears to be low, while the cervical cancer risk is reported to increase relative to the duration of use.34-37 This latter observation may be due to the greater likelihood of unprotected sex in women using a COC and exposure to multiple sexual partners in some cases, which may increase the likelihood of oncogenic human papillomavirus infection of the cervix. If a dermatologist elects to prescribe a COC to treat AV, it has been suggested that the patient also consult with her general practitioner or gynecologist to undergo pelvic and breast examinations and a Papanicolaou test.33 The recommendation for initial screening for cervical cancer is within 3 years of initiation of sexual intercourse or by 21 years of age, whichever is first.33,38,39

 

 

Combination oral contraceptives are not ideal for all adult women with AV. Absolute contraindications are pregnancy and history of thromboembolic, cardiac, or hepatic disease; in women aged 35 years and older who smoke, relative contraindications include hypertension, diabetes, migraines, breastfeeding, and current breast or liver cancer.33 In adult women with AV who have relative contra-indications but are likely to benefit from the use of a COC when other options are limited or not viable, consultation with a gynecologist is prudent. Other than rifamycin antibiotics (eg, rifampin) and griseofulvin, there is no definitive evidence that oral antibiotics (eg, tetracycline) or oral antifungal agents reduce the contraceptive efficacy of COCs, although cautions remain in print within some approved package inserts.8

Spironolactone

Available since 1957, spironolactone is an oral aldos-terone antagonist and potassium-sparing diuretic used to treat hypertension and congestive heart failure.9 Recognition of its antiandrogenic effects led to its use in dermatology to treat certain dermatologic disorders in women (eg, hirsutism, alopecia, AV).1,4,5,9,10 Spironolactone is not approved for AV by the FDA; therefore, available data from multiple independent studies and retrospective analyses that have been collectively reviewed support its efficacy when used as both monotherapy or in combination with other agents in adult women with AV, especially those with a U-shaped pattern and/or late-onset AV.9,40-43

Mechanism of Action

Spironolactone inhibits sebaceous gland activity through peripheral androgen receptor blockade, inhibition of 5α-reductase, decrease in androgen production, and increase in sex hormone–binding globulin.9,10,40

Therapeutic Benefits

Good to excellent improvement of AV in women, many of whom are postadolescent, has ranged from 66% to 100% in published reports9,40-43; however, inclusion and exclusion criteria, dosing regimens, and concomitant therapies were not usually controlled. Spironolactone has been used to treat AV in adult women as monotherapy or in combination with topical agents, oral antibiotics, and COCs.9,40-42 Additionally, dose-ranging studies have not been completed with spironolactone for AV.9,40 The suggested dose range is 50 mg to 200 mg daily; however, it usually is best to start at 50 mg daily and increase to 100 mg daily if clinical response is not adequate after 2 to 3 months. The gastrointestinal (GI) absorption of spironolactone is increased when ingested with a high-fat meal.9,10

Once effective control of AV is achieved, it is optimal to use the lowest dose needed to continue reasonable suppression of new AV lesions. There is no defined end point for spironolactone use in AV, with or without concurrent PCOS, as many adult women usually continue treatment with low-dose therapy because they experience marked flaring shortly after the drug is stopped.9

Risks and Contraindications

Side effects associated with spironolactone are dose related and include increased diuresis, migraines, menstrual irregularities, breast tenderness, gynecomastia, fatigue, and dizziness.9,10,40-44 Side effects (particularly menstrual irregularities and breast tenderness) are more common at doses higher than 100 mg daily, especially when used as monotherapy without concurrent use of a COC.9,40

Spironolactone-associated hyperkalemia is most clinically relevant in patients on higher doses (eg, 100–200 mg daily), in those with renal impairment and/or congestive heart failure, and when used concurrently with certain other medications. In any patient on spironolactone, the risk of clinically relevant hyperkalemia may be increased by coingestion of potassium supplements, potassium-based salt substitutes, potassium-sparing diuretics (eg, amiloride, triamterene); aldosterone antagonists and angiotensin-converting enzyme inhibitors (eg, lisinopril, benazepril); angiotensin II receptor blockers (eg, losartan, valsartan); and tri-methoprim (with or without sulfamethoxazole).8,9,40,45 Spironolactone may also increase serum levels of lithium or digoxin.9,40,45,46 For management of AV, it is best that spironolactone be avoided in patients taking any of these medications.9

In healthy adult women with AV who are not on medications or supplements that interact adversely with spironolactone, there is no definitive recommendation regarding monitoring of serum potassium levels during treatment with spironolactone, and it has been suggested that monitoring serum potassium levels in this subgroup is not necessary.47 However, each clinician is advised to choose whether or not they wish to obtain baseline and/or periodic serum potassium levels when prescribing spironolactone for AV based on their degree of comfort and the patient’s history. Baseline and periodic blood testing to evaluate serum electrolytes and renal function are reasonable, especially as adult women with AV are usually treated with spironolactone over a prolonged period of time.9

The FDA black box warning for spironolactone states that it is tumorigenic in chronic toxicity studies in rats and refers to exposures 25- to 100-fold higher than those administered to humans.9,48 Although continued vigilance is warranted, evaluation of large populations of women treated with spironolactone do not suggest an association with increased risk of breast cancer.49,50

 

 

Spironolactone is a category C drug and thus should be avoided during pregnancy, primarily due to animal data suggesting risks of hypospadias and feminization in male fetuses.9 Importantly, there is an absence of reports linking exposure during pregnancy with congenital defects in humans, including in 2 known cases of high-dose exposures for maternal Bartter syndrome.9

The active metabolite, canrenone, is known to be present in breast milk at 0.2% of the maternal daily dose, but breastfeeding is generally believed to be safe with spironolactone based on evidence to date.9

Oral Antibiotics

Oral antibiotic therapy may be used in combination with a topical regimen to treat AV in adult women, keeping in mind some important caveats.1-7 For instance, monotherapy with oral antibiotics should be avoided, and concomitant use of benzoyl peroxide is suggested to reduce emergence of antibiotic-resistant Propionibacterium acnes strains.3,4 A therapeutic exit plan also is suggested when prescribing oral antibiotics to limit treatment to 3 to 4 months, if possible, to help mitigate the emergence of antibiotic-resistant bacteria (eg, staphylococci and streptococci).3-5,51

Tetracyclines, especially doxycycline and minocycline, are the most commonly prescribed agents. Doxycycline use warrants patient education on measures to limit the risks of esophageal and GI side effects and phototoxicity; enteric-coated and small tablet formulations have been shown to reduce GI side effects, especially when administered with food.3,52-55 In addition to vestibular side effects and hyperpigmentation, minocycline may be associated with rare but potentially severe adverse reactions such as drug hypersensitivity syndrome, autoimmune hepatitis, and lupus-like syndrome, which are reported more commonly in women.5,52,54 Vestibular side effects have been shown to decrease with use of extended-release tablets with weight-based dosing.53

Oral Isotretinoin

Oral isotretinoin is well established as highly effective for treatment of severe, recalcitrant AV, including nodular acne on the face and trunk.4,56 Currently available oral isotretinoins are branded generic formulations based on the pharmacokinetic profile of the original brand (Accutane [Roche Pharmaceuticals]) and with the use of Lidose Technology (Absorica [Cipher Pharmaceuticals]), which substantially increases GI absorption of isotretinoin in the absence of ingestion with a high-calorie, high-fat meal.57 The short- and long-term efficacy, dosing regimens, safety considerations, and serious teratogenic risks for oral isotretinoin are well published.4,56-58 Importantly, oral isotretinoin must be prescribed with strict adherence to the federally mandated iPLEDGE risk management program.

Low-dose oral isotretinoin therapy (<0.5 mg/kg–1 mg/kg daily) administered over several months longer than conventional regimens (ie, 16–20 weeks) has been suggested with demonstrated efficacy.57 However, this approach is not optimal due to the lack of established sustained clearance of AV after discontinuation of therapy and the greater potential for exposure to isotretinoin during pregnancy. Recurrences of AV do occur after completion of isotretinoin therapy, especially if cumulative systemic exposure to the drug during the initial course of treatment was inadequate.56,57

Oral isotretinoin has been shown to be effective in AV in adult women with or without PCOS with 0.5 mg/kg to 1 mg/kg daily and a total cumulative exposure of 120 mg/kg to 150 mg/kg.59 In one study, the presence of PCOS and greater number of nodules at baseline were predictive of a higher risk of relapse during the second year posttreatment.59

Conclusion

All oral therapies that are used to treat AV in adult women warrant individual consideration of possible benefits versus risks. Careful attention to possible side effects, patient-related risk factors, and potential drug-drug interactions is important. End points of therapy are not well established, with the exception of oral isotretinoin therapy. Clinicians must use their judgment in each case along with obtaining feedback from patients regarding the selection of therapy after a discussion of the available options.

Selection of oral agents for treatment of AV in adult women is dependent on multiple factors including the patient’s age, medication history, child-bearing potential, clinical presentation, and treatment preference following a discussion of the anticipated benefits versus potential risks.1,2 In patients with the mixed inflammatory and comedonal clinical pattern of AV, oral antibiotics can be used concurrently with topical therapies when moderate to severe inflammatory lesions are noted.3,4 However, many adult women who had AV as teenagers have already utilized oral antibiotic therapies in the past and often are interested in alternative options, express concerns regarding antibiotic resistance, report a history of antibiotic-associated yeast infections or other side effects, and/or encounter issues related to drug-drug interactions.3,5-8 Oral hormonal therapies such as combination oral contraceptives (COCs) or spironolactone often are utilized to treat adult women with AV, sometimes in combination with each other or other agents. Combination oral contraceptives appear to be especially effective in the management of the U-shaped clinical pattern or predominantly inflammatory, late-onset AV.1,5,9,10 Potential warnings, contraindications, adverse effects, and drug-drug interactions are important to keep in mind when considering the use of oral hormonal therapies.8-10 Oral isotretinoin, which should be prescribed with strict adherence to the iPLEDGE™ program (https://www.ipledgeprogram.com/), remains a viable option for cases of severe nodular AV and selected cases of refractory inflammatory AV, especially when scarring and/or marked psychosocial distress are noted.1,2,5,11 Although it is recognized that adult women with AV typically present with either a mixed inflammatory and comedonal or U-shaped clinical pattern predominantly involving the lower face and anterolateral neck, the available data do not adequately differentiate the relative responsiveness of these clinical patterns to specific therapeutic agents.

Combination Oral Contraceptives

Combination oral contraceptives are commonly used to treat AV in adult women, including those without and those with measurable androgen excess (eg, polycystic ovary syndrome [PCOS]). Combination oral contraceptives contain ethinyl estradiol and a progestational agent (eg, progestin); the latter varies in terms of its nonselective receptor interactions and the relative magnitude or absence of androgenic effects.10,12,13 Although some COCs are approved by the US Food and Drug Administration (FDA) for AV, there is little data available to determine the comparative efficacy among these and other COCs.10,14 When choosing a COC for treatment of AV, it is best to select an agent whose effectiveness is supported by evidence from clinical studies.10,15

Mechanisms of Action

The reported mechanisms of action for COCs include inhibition of ovarian androgen production and ovulation through gonadotropin suppression; upregulated synthesis of sex hormone–binding globulin, which decreases free testosterone levels through receptor binding; and inhibition of 5α-reductase (by some progestins), which reduces conversion of testosterone to dihydrotestosterone, the active derivative that induces androgenic effects at peripheral target tissues.10,13,16,17

Therapeutic Benefits

Use of COCs to treat AV in adult women who do not have measurable androgen excess is most rational in patients who also desire a method of contraception. Multiple monotherapy studies have demonstrated the efficacy of COCs in the treatment of AV on the face and trunk.4,10,12,15,17,18 It may take a minimum of 3 monthly cycles of use before acne lesion counts begin to appreciably decrease.12,15,19-21 Initiating COC therapy during menstruation ensures the absence of pregnancy. Combination oral contraceptives may be used with other topical and oral therapies for AV.2,3,9,10 Potential ancillary benefits of COCs include normalization of the menstrual cycle; reduced premenstrual dysphoric disorder symptoms; and reduced risk of endometrial cancer (approximately 50%), ovarian cancer (approximately 40%), and colorectal cancer.22-24

Risks and Contraindications

It is important to consider the potential risks associated with the use of COCs, especially in women with AV who are not seeking a method of contraception. Side effects of COCs can include nausea, breast tenderness, breakthrough bleeding, and weight gain.25,26 Potential adverse associations of COCs are described in the Table. The major potential vascular associations include venous thromboembolism, myocardial infarction, and cerebrovascular accident, all of which are influenced by concurrent factors such as a history of smoking, age (≥35 years), and hypertension.27-32 It is recommended that blood pressure be measured before initiating COC therapy as part of the general examination.33

The potential increase in breast cancer risk appears to be low, while the cervical cancer risk is reported to increase relative to the duration of use.34-37 This latter observation may be due to the greater likelihood of unprotected sex in women using a COC and exposure to multiple sexual partners in some cases, which may increase the likelihood of oncogenic human papillomavirus infection of the cervix. If a dermatologist elects to prescribe a COC to treat AV, it has been suggested that the patient also consult with her general practitioner or gynecologist to undergo pelvic and breast examinations and a Papanicolaou test.33 The recommendation for initial screening for cervical cancer is within 3 years of initiation of sexual intercourse or by 21 years of age, whichever is first.33,38,39

 

 

Combination oral contraceptives are not ideal for all adult women with AV. Absolute contraindications are pregnancy and history of thromboembolic, cardiac, or hepatic disease; in women aged 35 years and older who smoke, relative contraindications include hypertension, diabetes, migraines, breastfeeding, and current breast or liver cancer.33 In adult women with AV who have relative contra-indications but are likely to benefit from the use of a COC when other options are limited or not viable, consultation with a gynecologist is prudent. Other than rifamycin antibiotics (eg, rifampin) and griseofulvin, there is no definitive evidence that oral antibiotics (eg, tetracycline) or oral antifungal agents reduce the contraceptive efficacy of COCs, although cautions remain in print within some approved package inserts.8

Spironolactone

Available since 1957, spironolactone is an oral aldos-terone antagonist and potassium-sparing diuretic used to treat hypertension and congestive heart failure.9 Recognition of its antiandrogenic effects led to its use in dermatology to treat certain dermatologic disorders in women (eg, hirsutism, alopecia, AV).1,4,5,9,10 Spironolactone is not approved for AV by the FDA; therefore, available data from multiple independent studies and retrospective analyses that have been collectively reviewed support its efficacy when used as both monotherapy or in combination with other agents in adult women with AV, especially those with a U-shaped pattern and/or late-onset AV.9,40-43

Mechanism of Action

Spironolactone inhibits sebaceous gland activity through peripheral androgen receptor blockade, inhibition of 5α-reductase, decrease in androgen production, and increase in sex hormone–binding globulin.9,10,40

Therapeutic Benefits

Good to excellent improvement of AV in women, many of whom are postadolescent, has ranged from 66% to 100% in published reports9,40-43; however, inclusion and exclusion criteria, dosing regimens, and concomitant therapies were not usually controlled. Spironolactone has been used to treat AV in adult women as monotherapy or in combination with topical agents, oral antibiotics, and COCs.9,40-42 Additionally, dose-ranging studies have not been completed with spironolactone for AV.9,40 The suggested dose range is 50 mg to 200 mg daily; however, it usually is best to start at 50 mg daily and increase to 100 mg daily if clinical response is not adequate after 2 to 3 months. The gastrointestinal (GI) absorption of spironolactone is increased when ingested with a high-fat meal.9,10

Once effective control of AV is achieved, it is optimal to use the lowest dose needed to continue reasonable suppression of new AV lesions. There is no defined end point for spironolactone use in AV, with or without concurrent PCOS, as many adult women usually continue treatment with low-dose therapy because they experience marked flaring shortly after the drug is stopped.9

Risks and Contraindications

Side effects associated with spironolactone are dose related and include increased diuresis, migraines, menstrual irregularities, breast tenderness, gynecomastia, fatigue, and dizziness.9,10,40-44 Side effects (particularly menstrual irregularities and breast tenderness) are more common at doses higher than 100 mg daily, especially when used as monotherapy without concurrent use of a COC.9,40

Spironolactone-associated hyperkalemia is most clinically relevant in patients on higher doses (eg, 100–200 mg daily), in those with renal impairment and/or congestive heart failure, and when used concurrently with certain other medications. In any patient on spironolactone, the risk of clinically relevant hyperkalemia may be increased by coingestion of potassium supplements, potassium-based salt substitutes, potassium-sparing diuretics (eg, amiloride, triamterene); aldosterone antagonists and angiotensin-converting enzyme inhibitors (eg, lisinopril, benazepril); angiotensin II receptor blockers (eg, losartan, valsartan); and tri-methoprim (with or without sulfamethoxazole).8,9,40,45 Spironolactone may also increase serum levels of lithium or digoxin.9,40,45,46 For management of AV, it is best that spironolactone be avoided in patients taking any of these medications.9

In healthy adult women with AV who are not on medications or supplements that interact adversely with spironolactone, there is no definitive recommendation regarding monitoring of serum potassium levels during treatment with spironolactone, and it has been suggested that monitoring serum potassium levels in this subgroup is not necessary.47 However, each clinician is advised to choose whether or not they wish to obtain baseline and/or periodic serum potassium levels when prescribing spironolactone for AV based on their degree of comfort and the patient’s history. Baseline and periodic blood testing to evaluate serum electrolytes and renal function are reasonable, especially as adult women with AV are usually treated with spironolactone over a prolonged period of time.9

The FDA black box warning for spironolactone states that it is tumorigenic in chronic toxicity studies in rats and refers to exposures 25- to 100-fold higher than those administered to humans.9,48 Although continued vigilance is warranted, evaluation of large populations of women treated with spironolactone do not suggest an association with increased risk of breast cancer.49,50

 

 

Spironolactone is a category C drug and thus should be avoided during pregnancy, primarily due to animal data suggesting risks of hypospadias and feminization in male fetuses.9 Importantly, there is an absence of reports linking exposure during pregnancy with congenital defects in humans, including in 2 known cases of high-dose exposures for maternal Bartter syndrome.9

The active metabolite, canrenone, is known to be present in breast milk at 0.2% of the maternal daily dose, but breastfeeding is generally believed to be safe with spironolactone based on evidence to date.9

Oral Antibiotics

Oral antibiotic therapy may be used in combination with a topical regimen to treat AV in adult women, keeping in mind some important caveats.1-7 For instance, monotherapy with oral antibiotics should be avoided, and concomitant use of benzoyl peroxide is suggested to reduce emergence of antibiotic-resistant Propionibacterium acnes strains.3,4 A therapeutic exit plan also is suggested when prescribing oral antibiotics to limit treatment to 3 to 4 months, if possible, to help mitigate the emergence of antibiotic-resistant bacteria (eg, staphylococci and streptococci).3-5,51

Tetracyclines, especially doxycycline and minocycline, are the most commonly prescribed agents. Doxycycline use warrants patient education on measures to limit the risks of esophageal and GI side effects and phototoxicity; enteric-coated and small tablet formulations have been shown to reduce GI side effects, especially when administered with food.3,52-55 In addition to vestibular side effects and hyperpigmentation, minocycline may be associated with rare but potentially severe adverse reactions such as drug hypersensitivity syndrome, autoimmune hepatitis, and lupus-like syndrome, which are reported more commonly in women.5,52,54 Vestibular side effects have been shown to decrease with use of extended-release tablets with weight-based dosing.53

Oral Isotretinoin

Oral isotretinoin is well established as highly effective for treatment of severe, recalcitrant AV, including nodular acne on the face and trunk.4,56 Currently available oral isotretinoins are branded generic formulations based on the pharmacokinetic profile of the original brand (Accutane [Roche Pharmaceuticals]) and with the use of Lidose Technology (Absorica [Cipher Pharmaceuticals]), which substantially increases GI absorption of isotretinoin in the absence of ingestion with a high-calorie, high-fat meal.57 The short- and long-term efficacy, dosing regimens, safety considerations, and serious teratogenic risks for oral isotretinoin are well published.4,56-58 Importantly, oral isotretinoin must be prescribed with strict adherence to the federally mandated iPLEDGE risk management program.

Low-dose oral isotretinoin therapy (<0.5 mg/kg–1 mg/kg daily) administered over several months longer than conventional regimens (ie, 16–20 weeks) has been suggested with demonstrated efficacy.57 However, this approach is not optimal due to the lack of established sustained clearance of AV after discontinuation of therapy and the greater potential for exposure to isotretinoin during pregnancy. Recurrences of AV do occur after completion of isotretinoin therapy, especially if cumulative systemic exposure to the drug during the initial course of treatment was inadequate.56,57

Oral isotretinoin has been shown to be effective in AV in adult women with or without PCOS with 0.5 mg/kg to 1 mg/kg daily and a total cumulative exposure of 120 mg/kg to 150 mg/kg.59 In one study, the presence of PCOS and greater number of nodules at baseline were predictive of a higher risk of relapse during the second year posttreatment.59

Conclusion

All oral therapies that are used to treat AV in adult women warrant individual consideration of possible benefits versus risks. Careful attention to possible side effects, patient-related risk factors, and potential drug-drug interactions is important. End points of therapy are not well established, with the exception of oral isotretinoin therapy. Clinicians must use their judgment in each case along with obtaining feedback from patients regarding the selection of therapy after a discussion of the available options.

References
  1. Holzmann R, Shakery K. Postadolescent acne in females. Skin Pharmacol Physiol. 2014;27(suppl 1):3-8.
  2. Villasenor J, Berson DS, Kroshinsky D. Treatment guidelines in adult women. In: Shalita AR, Del Rosso JQ, Webster GF, eds. Acne Vulgaris. London, United Kingdom: Informa Healthcare; 2011:198-207.
  3. Del Rosso JQ, Kim G. Optimizing use of oral antibiotics in acne vulgaris. Dermatol Clin. 2009;27:33-42.
  4. Gollnick H, Cunliffe W, Berson D, et al. Management of acne: report from a Global Alliance to Improve Outcomes in Acne. J Am Acad Dermatol. 2003;49(suppl 1):S1-S37.
  5. Fisk WA, Lev-Tov HA, Sivamani RK. Epidemiology and management of acne in adult women. Curr Derm Rep. 2014;3:29-39.
  6. Del Rosso JQ, Leyden JJ. Status report on antibiotic resistance: implications for the dermatologist. Dermatol Clin. 2007;25:127-132.
  7. Bowe WP, Leyden JJ. Clinical implications of antibiotic resistance: risk of systemic infection from Staphylococcus and Streptococcus. In: Shalita AR, Del Rosso JQ, Webster GF, eds. Acne Vulgaris. London, United Kingdom: Informa Healthcare; 2011:125-133.
  8. Del Rosso JQ. Oral antibiotic drug interactions of clinical significance to dermatologists. Dermatol Clin. 2009;27:91-94.
  9. Kim GK, Del Rosso JQ. Oral spironolactone in post-teenage female patients with acne vulgaris: practical considerations for the clinician based on current data and clinical experience. J Clin Aesthet Dermatol. 2012;5:37-50.
  10. Keri J, Berson DS, Thiboutot DM. Hormonal treatment of acne in women. In: Shalita AR, Del Rosso JQ, Webster GF, eds. Acne Vulgaris. London, United Kingdom: Informa Healthcare; 2011:146-155.
  11. American Academy of Dermatology. Position statement on isotretinoin. AAD Web site. https://www.aad.org /Forms/Policies/Uploads/PS/PS-Isotretinoin.pdf. Updated November 13, 2010. Accessed October 28, 2015.
  12. Arowojolu AO, Gallo MF, Lopez LM, et al. Combined oral contraceptive pills for treatment of acne. Cochrane Database Syst Rev. June 2012;7:CD004425.
  13. Sitruk-Ware R. Pharmacology of different progestogens: the special case of drospirenone. Climacteric. 2005;8 (suppl 3):4-12.
  14. Arowojolu AO, Gallo MF, Lopez LM, et al. Combined oral contraceptive pills for the treatment of acne. Cochrane Database Syst Rev. July 2012;7:CD004425.
  15. Thiboutot D, Archer DF, Lemay A, et al. A randomized, controlled trial of a low-dose contraceptive containing 20 microg of ethinyl estradiol and 100 microg of levonogestrel for acne treatment. Fertil Steril. 2001;76:461-468.
  16. Koulianos GT. Treatment of acne with oral contraceptives: criteria for pill selection. Cutis. 2000;66:281-286.
  17. Rabe T, Kowald A, Ortmann J, et al. Inhibition of skin 5-alpha reductase by oral contraceptive progestins in vitro. Gynecol Endocrinol. 2000;14:223-230.
  18. Palli MB, Reyes-Habito CM, Lima XT, et al. A single-center, randomized double-blind, parallel-group study to examine the safety and efficacy of 3mg drospirenone/0.02mg ethinyl estradiol compared with placebo in the treatment of moderate truncal acne vulgaris. J Drugs Dermatol. 2013;12:633-637.
  19. Koltun W, Maloney JM, Marr J, et al. Treatment of moderate acne vulgaris using a combined oral contraceptive containing ethinylestradiol 20 μg plus drospirenone 3 mg administered in a 24/4 regimen: a pooled analysis. Eur J Obstet Gynecol Reprod Biol. 2011;155:171-175.
  20. Maloney JM, Dietze P, Watson D, et al. A randomized controlled trial of a low-dose combined oral contraceptive containing 3 mg drospirenone plus 20 μg ethinylestradiol in the treatment of acne vulgaris: lesion counts, investigator ratings and subject self-assessment. J Drugs Dermatol. 2009;8:837-844.
  21. Lucky AW, Koltun W, Thiboutot D, et al. A combined oral contraceptive containing 3-mg drospirenone/20-μg ethinyl estradiol in the treatment of acne vulgaris: a randomized, double-blind, placebo-controlled study evaluating lesion counts and participant self-assessment. Cutis. 2008;82:143-150.
  22. Burkman R, Schlesselman JJ, Zieman M. Safety concerns and health benefits associated with oral contraception. Am J Obstet Gynecol. 2004;190(suppl 4):S5-S22.
  23. Maguire K, Westhoff C. The state of hormonal contraception today: established and emerging noncontraceptive health benefits. Am J Obstet Gynecol. 2011;205 (suppl 4):S4-S8.
  24. Weiss NS, Sayvetz TA. Incidence of endometrial cancer in relation to the use of oral contraceptives. N Engl J Med. 1980;302:551-554.
  25. Tyler KH, Zirwas MJ. Contraception and the dermatologist. J Am Acad Dermatol. 2013;68:1022-1029.
  26. Gallo MF, Lopez LM, Grimes DA, et al. Combination contraceptives: effects on weight. Cochrane Database Syst Rev. 2008;4:CD003987.
  27. de Bastos M, Stegeman BH, Rosendaal FR, et al. Combined oral contraceptives: venous thrombosis. Cochrane Database Syst Rev. 2014;3:CD010813.
  28. Raymond EG, Burke AE, Espey E. Combined hormonal contraceptives and venous thromboembolism: putting the risks into perspective. Obstet Gynecol. 2012;119:1039-1044.
  29. Jick SS, Hernandez RK. Risk of non-fatal venous thromboembolism in women using oral contraceptives containing drospirenone compared with women using oral contraceptives containing levonorgestrel: case-control study using United States claims data. BMJ. 2011;342:d2151.
  30. US Food and Drug Administration Office of Surveillance and Epidemiology. Combined hormonal contraceptives (CHCs) and the risk of cardiovascular disease endpoints. US Food and Drug Administration Web site. http://www.fda.gov/downloads/Drugs /Drug Safety/UCM277384.pdf. Accessed October 28, 2015.
  31. The American College of Obstetricians and Gynecologists Committee on Gynecologic Practice. Risk of venous thromboembolism among users of drospirenone-containing oral contraceptive pills. Obstet Gynecol. 2012;120:1239-1242.
  32. World Health Organization. Cardiovascular Disease and Steroid Hormone Contraception: Report of a WHO Scientific Group. Geneva, Switzerland: World Health Organization; 1998. Technical Report Series 877.
  33. Frangos JE, Alavian CN, Kimball AB. Acne and oral contraceptives: update on women’s health screening guidelines. J Am Acad Dermatol. 2008;58:781-786.
  34. Collaborative Group on Hormonal Factors in Breast Cancer. Breast cancer and hormonal contraceptives: collaborative reanalysis of individual data on 53 297 women with breast cancer and 100 239 women without breast cancer from 54 epidemiological studies. Lancet. 1996;347:1713-1727.
  35. Gierisch JM, Coeytaux RR, Urrutia RP, et al. Oral contraceptive use and risk of breast, cervical, colorectal, and endometrial cancers: a systematic review. Cancer Epidemiol Biomarkers Prev. 2013;22:1931-1943.
  36. International Collaboration of Epidemiological Studies of Cervical Cancer. Cervical cancer and hormonal contraceptives: collaborative reanalysis of individual data for 16 573 women with cervical cancer and 35 509 women without cervical cancer from 24 epidemiological studies. Lancet. 2007;370:1609-1621.
  37. Agostino H, Di Meglio G. Low-dose oral contraceptives in adolescents: how low can you go? J Pediatr Adolesc Gynecol. 2010;23:195-201.
  38. Buzney E, Sheu J, Buzney C, et al. Polycystic ovary syndrome: a review for dermatologists: part II. Treatment. J Am Acad Dermatol. 2014;71:859.e1-859.e15.
  39. Stewart FH, Harper CC, Ellertson CE, et al. Clinical breast and pelvic examination requirements for hormonal contraception: current practice vs evidence. JAMA. 2001;285:2232-2239.
  40. Sawaya ME, Somani N. Antiandrogens and androgen inhibitors. In: Wolverton SE, ed. Comprehensive Dermatologic Drug Therapy. 3rd ed. Philadelpha, PA: Saunders; 2013:361-374.
  41. Muhlemann MF, Carter GD, Cream JJ, et al. Oral spironolactone: an effective treatment for acne vulgaris in women. Br J Dermatol. 1986;115:227-232.
  42. Shaw JC. Low-dose adjunctive spironolactone in the treatment of acne in women: a retrospective analysis of 85 consecutively treated patients. J Am Acad Dermatol. 2000;43:498-502.
  43. Sato K, Matsumoto D, Iizuka F, et al. Anti-androgenic therapy using oral spironolactone for acne vulgaris in Asians. Aesth Plast Surg. 2006;30:689-694.
  44. Shaw JC, White LE. Long-term safety of spironolactone in acne: results of an 8-year follow-up study. J Cutan Med Surg. 2002;6:541-545.
  45. Stockley I. Antihypertensive drug interactions. In: Stockley I, ed. Drug Interactions. 5th ed. London, United Kingdom: Pharmaceutical Press; 1999:335-347.
  46. Antoniou T, Gomes T, Mamdani MM, et al. Trimethoprim-sulfamethoxazole induced hyperkalaemia in elderly patients receiving spironolactone: nested case-control study. BMJ. 2011;343:d5228.
  47. Plovanich M, Weng QY, Mostaghimi A. Low usefulness of potassium monitoring among healthy young women taking spironolactone for acne. JAMA Dermatol. 2015;151:941-944.
  48. Aldactone [package insert]. New York, NY: Pfizer Inc; 2008.
  49. Biggar RJ, Andersen EW, Wohlfahrt J, et al. Spironolactone use and the risk of breast and gynecologic cancers. Cancer Epidemiol. 2013;37:870-875.
  50. Mackenzie IS, Macdonald TM, Thompson A, et al. Spironolactone and risk of incident breast cancer in women older than 55 years: retrospective, matched cohort study. BMJ. 2012;345:e4447.
  51. Dreno B, Thiboutot D, Gollnick H, et al. Antibiotic stewardship in dermatology: limiting antibiotic use in acne. Eur J Dermatol. 2014;24:330-334.
  52. Kim S, Michaels BD, Kim GK, et al. Systemic antibacterial agents. In: Wolverton SE, ed. Comprehensive Dermatologic Drug Therapy. 3rd ed. Philadelpha, PA: Saunders; 2013:61-97.
  53. Leyden JJ, Del Rosso JQ. Oral antibiotic therapy for acne vulgaris: pharmacokinetic and pharmacodynamics perspectives. J Clin Aesthet Dermatol. 2011;4:40-47.
  54. Del Rosso JQ. Oral antibiotics. In: Shalita AR, Del Rosso JQ, Webster GF, eds. Acne Vulgaris. London, United Kingdom: Informa Healthcare; 2011:113-124.
  55. Del Rosso JQ. Oral doxycycline in the management of acne vulgaris: current perspectives on clinical use and recent findings with a new double-scored small tablet formulation. J Clin Aesthet Dermatol. 2015;8:19-26.
  56. Osofsky MG, Strauss JS. Isotretinoin. In: Shalita AR, Del Rosso JQ, Webster GF, eds. Acne Vulgaris. London, United Kingdom: Informa Healthcare; 2011:134-145.
  57. Leyden JJ, Del Rosso JQ, Baum EW. The use of isotretinoin in the treatment of acne vulgaris: clinical considerations and future directions. J Clin Aesthet Dermatol. 2014;7(suppl 2):S3-S21.
  58. Patton TJ, Ferris LK. Systemic retinoids. In: Wolverton SE, ed. Comprehensive Dermatologic Drug Therapy. 3rd ed. Philadelpha, PA: Saunders; 2013:252-268.
  59. Cakir GA, Erdogan FG, Gurler A. Isotretinoin treatment in nodulocystic acne with and without polycystic ovary syndrome: efficacy and determinants of relapse. Int J Dermatol. 2013;52:371-376.
References
  1. Holzmann R, Shakery K. Postadolescent acne in females. Skin Pharmacol Physiol. 2014;27(suppl 1):3-8.
  2. Villasenor J, Berson DS, Kroshinsky D. Treatment guidelines in adult women. In: Shalita AR, Del Rosso JQ, Webster GF, eds. Acne Vulgaris. London, United Kingdom: Informa Healthcare; 2011:198-207.
  3. Del Rosso JQ, Kim G. Optimizing use of oral antibiotics in acne vulgaris. Dermatol Clin. 2009;27:33-42.
  4. Gollnick H, Cunliffe W, Berson D, et al. Management of acne: report from a Global Alliance to Improve Outcomes in Acne. J Am Acad Dermatol. 2003;49(suppl 1):S1-S37.
  5. Fisk WA, Lev-Tov HA, Sivamani RK. Epidemiology and management of acne in adult women. Curr Derm Rep. 2014;3:29-39.
  6. Del Rosso JQ, Leyden JJ. Status report on antibiotic resistance: implications for the dermatologist. Dermatol Clin. 2007;25:127-132.
  7. Bowe WP, Leyden JJ. Clinical implications of antibiotic resistance: risk of systemic infection from Staphylococcus and Streptococcus. In: Shalita AR, Del Rosso JQ, Webster GF, eds. Acne Vulgaris. London, United Kingdom: Informa Healthcare; 2011:125-133.
  8. Del Rosso JQ. Oral antibiotic drug interactions of clinical significance to dermatologists. Dermatol Clin. 2009;27:91-94.
  9. Kim GK, Del Rosso JQ. Oral spironolactone in post-teenage female patients with acne vulgaris: practical considerations for the clinician based on current data and clinical experience. J Clin Aesthet Dermatol. 2012;5:37-50.
  10. Keri J, Berson DS, Thiboutot DM. Hormonal treatment of acne in women. In: Shalita AR, Del Rosso JQ, Webster GF, eds. Acne Vulgaris. London, United Kingdom: Informa Healthcare; 2011:146-155.
  11. American Academy of Dermatology. Position statement on isotretinoin. AAD Web site. https://www.aad.org /Forms/Policies/Uploads/PS/PS-Isotretinoin.pdf. Updated November 13, 2010. Accessed October 28, 2015.
  12. Arowojolu AO, Gallo MF, Lopez LM, et al. Combined oral contraceptive pills for treatment of acne. Cochrane Database Syst Rev. June 2012;7:CD004425.
  13. Sitruk-Ware R. Pharmacology of different progestogens: the special case of drospirenone. Climacteric. 2005;8 (suppl 3):4-12.
  14. Arowojolu AO, Gallo MF, Lopez LM, et al. Combined oral contraceptive pills for the treatment of acne. Cochrane Database Syst Rev. July 2012;7:CD004425.
  15. Thiboutot D, Archer DF, Lemay A, et al. A randomized, controlled trial of a low-dose contraceptive containing 20 microg of ethinyl estradiol and 100 microg of levonogestrel for acne treatment. Fertil Steril. 2001;76:461-468.
  16. Koulianos GT. Treatment of acne with oral contraceptives: criteria for pill selection. Cutis. 2000;66:281-286.
  17. Rabe T, Kowald A, Ortmann J, et al. Inhibition of skin 5-alpha reductase by oral contraceptive progestins in vitro. Gynecol Endocrinol. 2000;14:223-230.
  18. Palli MB, Reyes-Habito CM, Lima XT, et al. A single-center, randomized double-blind, parallel-group study to examine the safety and efficacy of 3mg drospirenone/0.02mg ethinyl estradiol compared with placebo in the treatment of moderate truncal acne vulgaris. J Drugs Dermatol. 2013;12:633-637.
  19. Koltun W, Maloney JM, Marr J, et al. Treatment of moderate acne vulgaris using a combined oral contraceptive containing ethinylestradiol 20 μg plus drospirenone 3 mg administered in a 24/4 regimen: a pooled analysis. Eur J Obstet Gynecol Reprod Biol. 2011;155:171-175.
  20. Maloney JM, Dietze P, Watson D, et al. A randomized controlled trial of a low-dose combined oral contraceptive containing 3 mg drospirenone plus 20 μg ethinylestradiol in the treatment of acne vulgaris: lesion counts, investigator ratings and subject self-assessment. J Drugs Dermatol. 2009;8:837-844.
  21. Lucky AW, Koltun W, Thiboutot D, et al. A combined oral contraceptive containing 3-mg drospirenone/20-μg ethinyl estradiol in the treatment of acne vulgaris: a randomized, double-blind, placebo-controlled study evaluating lesion counts and participant self-assessment. Cutis. 2008;82:143-150.
  22. Burkman R, Schlesselman JJ, Zieman M. Safety concerns and health benefits associated with oral contraception. Am J Obstet Gynecol. 2004;190(suppl 4):S5-S22.
  23. Maguire K, Westhoff C. The state of hormonal contraception today: established and emerging noncontraceptive health benefits. Am J Obstet Gynecol. 2011;205 (suppl 4):S4-S8.
  24. Weiss NS, Sayvetz TA. Incidence of endometrial cancer in relation to the use of oral contraceptives. N Engl J Med. 1980;302:551-554.
  25. Tyler KH, Zirwas MJ. Contraception and the dermatologist. J Am Acad Dermatol. 2013;68:1022-1029.
  26. Gallo MF, Lopez LM, Grimes DA, et al. Combination contraceptives: effects on weight. Cochrane Database Syst Rev. 2008;4:CD003987.
  27. de Bastos M, Stegeman BH, Rosendaal FR, et al. Combined oral contraceptives: venous thrombosis. Cochrane Database Syst Rev. 2014;3:CD010813.
  28. Raymond EG, Burke AE, Espey E. Combined hormonal contraceptives and venous thromboembolism: putting the risks into perspective. Obstet Gynecol. 2012;119:1039-1044.
  29. Jick SS, Hernandez RK. Risk of non-fatal venous thromboembolism in women using oral contraceptives containing drospirenone compared with women using oral contraceptives containing levonorgestrel: case-control study using United States claims data. BMJ. 2011;342:d2151.
  30. US Food and Drug Administration Office of Surveillance and Epidemiology. Combined hormonal contraceptives (CHCs) and the risk of cardiovascular disease endpoints. US Food and Drug Administration Web site. http://www.fda.gov/downloads/Drugs /Drug Safety/UCM277384.pdf. Accessed October 28, 2015.
  31. The American College of Obstetricians and Gynecologists Committee on Gynecologic Practice. Risk of venous thromboembolism among users of drospirenone-containing oral contraceptive pills. Obstet Gynecol. 2012;120:1239-1242.
  32. World Health Organization. Cardiovascular Disease and Steroid Hormone Contraception: Report of a WHO Scientific Group. Geneva, Switzerland: World Health Organization; 1998. Technical Report Series 877.
  33. Frangos JE, Alavian CN, Kimball AB. Acne and oral contraceptives: update on women’s health screening guidelines. J Am Acad Dermatol. 2008;58:781-786.
  34. Collaborative Group on Hormonal Factors in Breast Cancer. Breast cancer and hormonal contraceptives: collaborative reanalysis of individual data on 53 297 women with breast cancer and 100 239 women without breast cancer from 54 epidemiological studies. Lancet. 1996;347:1713-1727.
  35. Gierisch JM, Coeytaux RR, Urrutia RP, et al. Oral contraceptive use and risk of breast, cervical, colorectal, and endometrial cancers: a systematic review. Cancer Epidemiol Biomarkers Prev. 2013;22:1931-1943.
  36. International Collaboration of Epidemiological Studies of Cervical Cancer. Cervical cancer and hormonal contraceptives: collaborative reanalysis of individual data for 16 573 women with cervical cancer and 35 509 women without cervical cancer from 24 epidemiological studies. Lancet. 2007;370:1609-1621.
  37. Agostino H, Di Meglio G. Low-dose oral contraceptives in adolescents: how low can you go? J Pediatr Adolesc Gynecol. 2010;23:195-201.
  38. Buzney E, Sheu J, Buzney C, et al. Polycystic ovary syndrome: a review for dermatologists: part II. Treatment. J Am Acad Dermatol. 2014;71:859.e1-859.e15.
  39. Stewart FH, Harper CC, Ellertson CE, et al. Clinical breast and pelvic examination requirements for hormonal contraception: current practice vs evidence. JAMA. 2001;285:2232-2239.
  40. Sawaya ME, Somani N. Antiandrogens and androgen inhibitors. In: Wolverton SE, ed. Comprehensive Dermatologic Drug Therapy. 3rd ed. Philadelpha, PA: Saunders; 2013:361-374.
  41. Muhlemann MF, Carter GD, Cream JJ, et al. Oral spironolactone: an effective treatment for acne vulgaris in women. Br J Dermatol. 1986;115:227-232.
  42. Shaw JC. Low-dose adjunctive spironolactone in the treatment of acne in women: a retrospective analysis of 85 consecutively treated patients. J Am Acad Dermatol. 2000;43:498-502.
  43. Sato K, Matsumoto D, Iizuka F, et al. Anti-androgenic therapy using oral spironolactone for acne vulgaris in Asians. Aesth Plast Surg. 2006;30:689-694.
  44. Shaw JC, White LE. Long-term safety of spironolactone in acne: results of an 8-year follow-up study. J Cutan Med Surg. 2002;6:541-545.
  45. Stockley I. Antihypertensive drug interactions. In: Stockley I, ed. Drug Interactions. 5th ed. London, United Kingdom: Pharmaceutical Press; 1999:335-347.
  46. Antoniou T, Gomes T, Mamdani MM, et al. Trimethoprim-sulfamethoxazole induced hyperkalaemia in elderly patients receiving spironolactone: nested case-control study. BMJ. 2011;343:d5228.
  47. Plovanich M, Weng QY, Mostaghimi A. Low usefulness of potassium monitoring among healthy young women taking spironolactone for acne. JAMA Dermatol. 2015;151:941-944.
  48. Aldactone [package insert]. New York, NY: Pfizer Inc; 2008.
  49. Biggar RJ, Andersen EW, Wohlfahrt J, et al. Spironolactone use and the risk of breast and gynecologic cancers. Cancer Epidemiol. 2013;37:870-875.
  50. Mackenzie IS, Macdonald TM, Thompson A, et al. Spironolactone and risk of incident breast cancer in women older than 55 years: retrospective, matched cohort study. BMJ. 2012;345:e4447.
  51. Dreno B, Thiboutot D, Gollnick H, et al. Antibiotic stewardship in dermatology: limiting antibiotic use in acne. Eur J Dermatol. 2014;24:330-334.
  52. Kim S, Michaels BD, Kim GK, et al. Systemic antibacterial agents. In: Wolverton SE, ed. Comprehensive Dermatologic Drug Therapy. 3rd ed. Philadelpha, PA: Saunders; 2013:61-97.
  53. Leyden JJ, Del Rosso JQ. Oral antibiotic therapy for acne vulgaris: pharmacokinetic and pharmacodynamics perspectives. J Clin Aesthet Dermatol. 2011;4:40-47.
  54. Del Rosso JQ. Oral antibiotics. In: Shalita AR, Del Rosso JQ, Webster GF, eds. Acne Vulgaris. London, United Kingdom: Informa Healthcare; 2011:113-124.
  55. Del Rosso JQ. Oral doxycycline in the management of acne vulgaris: current perspectives on clinical use and recent findings with a new double-scored small tablet formulation. J Clin Aesthet Dermatol. 2015;8:19-26.
  56. Osofsky MG, Strauss JS. Isotretinoin. In: Shalita AR, Del Rosso JQ, Webster GF, eds. Acne Vulgaris. London, United Kingdom: Informa Healthcare; 2011:134-145.
  57. Leyden JJ, Del Rosso JQ, Baum EW. The use of isotretinoin in the treatment of acne vulgaris: clinical considerations and future directions. J Clin Aesthet Dermatol. 2014;7(suppl 2):S3-S21.
  58. Patton TJ, Ferris LK. Systemic retinoids. In: Wolverton SE, ed. Comprehensive Dermatologic Drug Therapy. 3rd ed. Philadelpha, PA: Saunders; 2013:252-268.
  59. Cakir GA, Erdogan FG, Gurler A. Isotretinoin treatment in nodulocystic acne with and without polycystic ovary syndrome: efficacy and determinants of relapse. Int J Dermatol. 2013;52:371-376.
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Status Report From the American Acne & Rosacea Society on Medical Management of Acne in Adult Women, Part 3: Oral Therapies
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Status Report From the American Acne & Rosacea Society on Medical Management of Acne in Adult Women, Part 3: Oral Therapies
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acne vulgaris, oral contraception, women, antibiotics
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acne vulgaris, oral contraception, women, antibiotics
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Practice Points

  • Use of combination oral contraceptives to treat acne vulgaris (AV) in adult women who do not have measurable androgen excess is most rational in patients who also desire a method of contraception.
  • Spironolactone is widely accepted as an oral agent that can be effective in treating adult women with AV and may be used in combination with other therapies.
  • Monotherapy with oral antibiotics should be avoided in the treatment of adult women with AV, and concomitant use of benzoyl peroxide is suggested to reduce emergence of antibiotic-resistant Propionibacterium acnes strains.
  • Oral isotretinoin use in adult women with AV warrants strict adherence to pregnancy prevention measures and requirements set forth by the federally mandated iPLEDGE™ risk management program.
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Status Report From the American Acne & Rosacea Society on Medical Management of Acne in Adult Women, Part 1: Overview, Clinical Characteristics, and Laboratory Evaluation

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Status Report From the American Acne & Rosacea Society on Medical Management of Acne in Adult Women, Part 1: Overview, Clinical Characteristics, and Laboratory Evaluation
Author(s)
James Q. Del Rosso, DO
Julie C. Harper, MD
Emmy M. Graber, MD, MBA
Diane Thiboutot, MD
Nanette B. Silverberg, MD
Dawn Zhang Eichenfield, PhD
Lawrence F. Eichenfield, MD

It was not long ago that acne vulgaris (AV) was commonly considered to be a skin disease that affected teenagers with little attention given to preadolescent and postadolescent AV. This perspective has changed, with more attention being given to AV across a broad range of affected 
age groups, including preadolescent, adolescent, and postadolescent subgroups.1-5 Earlier onset of adrenarche has led to earlier development of AV in many young girls, with a higher range of dehydroepiandrosterone sulfate (DHEAS) levels observed overall in those with AV as compared to a normal age-matched population.3,4 At the other end of the age spectrum, AV is a common phenomenon in adult females, with at least half of women estimated to exhibit some form of AV.1,2,5-8 Based on a 
large survey of females and males (N=1013), the prevalence of AV in adult females has been reported to be 50.9%, 35.2%, 26.3%, and 15.3% among women aged 20 to 29 years, 30 to 39 years, 40 to 49 years, and 50 years and older, respectively.2 Acne vulgaris that persists beyond adolescence into adulthood is termed persistent acne, or early-onset acne, and the development of AV in women 25 years and older who have not previously been affected by AV has been termed late-onset acne.6,8,9 Publications on the management of AV in adult women have focused primarily on systemic hormonal therapies; however, topical therapies more recently have received greater attention in this subpopulation9-12 and will be discussed in part 2 of this series. Because data on AV in women are 
limited primarily to involvement of the face and neck region, this article does not address truncal AV unless otherwise specified. Table 1 depicts factors that can influence the management of AV in adult women.

Visible Patterns and Considerations for Clinical Evaluation 


Clinical Patterns

Although epidemiologic and demographic data are limited in the subpopulation of women with AV, it is reported that females account for up to 82% of adults with AV, with approximately 75% presenting with AV that is clinically similar to their disease course in adolescence.2,5,13 Among those women with persistent AV, some state that their AV is worse compared to adolescence, while others report it is not as severe. The pattern of AV often is similar to that seen in adolescence, presenting as mixed comedonal and inflammatory papular/pustular lesions diffusely distributed on the face; in other cases, a more selectively distributed U-shaped pattern is noted, characterized predominantly by inflammatory papules and/or nodules involving the lower cheeks and jawline margin, with lesions also commonly noted on the anterior and lateral neck.5,8,9,13-16 A U-shaped pattern is believed to be more common in late-onset AV, often with persistence into the mid-40s.1,15,17 It is important to emphasize the need for additional studies on the demographics and clinical characteristics of AV in adult females, especially correlations between onset, age, and clinical patterns of AV.

An international, prospective, observational study assessed the clinical characteristics of AV in adults (aged ≥25 years) at a dermatology visit for acne (N=374).16 Participants who were under management for their AV showed severity grades of mild (clear/almost clear) in 47.3% of cases. Involvement of multiple facial sites—cheeks, forehead, mandibular region, and temples—was noted in 89.8% of women, often with both inflammatory and comedonal lesions, which is a pattern similar to adolescent AV. Inflammatory lesions alone were observed in 6.4% of women, 17.1% had comedonal AV only, 
and truncal AV was present in 48.4%.16 Additional well-designed studies are needed to determine if this study reflects an accurate qualitative and 
quantitative depiction of the spectrum of AV in adult females.

Mandibular Pattern

In the observational study of AV in adults, AV localized to the mandibular area was noted in only 11.2% of participants.16 Women with localized mandibular AV were more likely than women without localized AV to be employed, noted greater daily stress levels, and tended to report more psychologically stressful jobs. Interestingly, the subgroup with mandibular acne alone was much less likely 
to exhibit a global severity grade of moderate or higher (7.1% vs 50.1%), truncal acne 
(19.0% vs 51.9%), postinflammatory hyperpigmentation (23.8% vs 51.9%), and erythema (19.0% vs 48.4%), suggesting a unique subset of AV presentation.16

Ethnicity/Skin Color

Women of all ethnicities and skin types may be affected by AV.1,18-20 Earlier age of onset of AV has been suggested in white women; however, earlier onset of adrenarche may be more frequent in black girls, which supports an earlier age of onset of AV in this subpopulation.15-17 Women with skin of color usually express greater concern with persistent dyschromia at sites where lesions have resolved, and presence of acne scars is a concern among women regardless of skin color, ethnicity, or race.18,20-22

 

 

Scarring

Acne scarring has been noted to affect up to 
three-fourths of adult women in one report17 and 
often is stated by patients to be a cause of concern 
and frustration.1,5,17

Perimenstrual Flaring

Flaring associated with menses is commonly reported in adult females with AV, with 56%, 17%, and 
3% of women in one study (n=230) reporting worsening before, during, or after menses, respectively.21

External Factors

Comedogenic products used for skin care, cover-up makeup, or hair care may be important to consider in selected cases as potential etiologic or exacerbating factors in adult females with AV; they also may be used in the management of AV.23-25 Adult females often are perplexed and frustrated by the presence of AV after their 
teenaged years and anxiously wonder about or search for the potential causes. Many women use cosmetic products to cover up facial AV.5,23-25 Therefore, even if skin care or personal hygiene products or makeup are not believed to be an etiologic factor, many patients appreciate that their dermatologist addressed skin care and cosmetics as a component of AV management and provided appropriate recommendations.5,13

Ingestion of dietary supplements containing whey protein have been associated with precipitation of AV.26,27 Diets with specific content characteristics have been implicated as potential etiologic or exacerbating factors for AV; however, data are limited and specific recommendations remain elusive at present. Individual cases may warrant consideration of dietary factors, especially when treatment resistance is noted.28 Importantly, progestin-only contraceptives (ie, injectables, intrauterine devices) also can exacerbate or induce AV.29

Hyperandrogenism

Although most adult females with AV are reported to have normal serum androgen levels when tested, it is important to explore potential signs and symptoms that are suggestive of underlying hyperandrogenism through both the patient’s history and physical examination.9-11,21,29-33 Some investigators have suggested that underlying peripheral hyperandrogenism is the leading cause of AV in adult females, 
with or without concurrent polycystic ovarian syndrome (PCOS), though it is believed that most women with AV exhibit normal results when 
undergoing laboratory testing for androgen excess.10,11,21,29,30 Nevertheless, it is important to consider the possibility of underlying causes of androgen excess (Table 2), the most common being PCOS and late-onset congenital adrenal hyperplasia; an androgen-secreting tumor is less common.11,29-33 It is suggested that screening for underlying endocrinopathy should be conducted in women presenting with (1) AV recalcitrant to conventional treatment, (2) sudden emergence of severe AV, 
(3) concurrent signs/symptoms of androgen 
excess, and/or (4) AV relapse shortly after isotretinoin therapy.7,11,16,33

Hirsutism and acanthosis nigricans have been reported to be more reliable predictors of hyperandrogenism than androgenic alopecia.21 Although it may be subtle in some cases, acanthosis nigricans is harder to camouflage, so the clinician can usually detect it if a thorough physical examination is performed. However, a patient may not voluntarily report to the clinician and their staff that she has hair removed, so despite a thorough examination, the clinician may not detect hirsutism. Therefore, it is important to inquire directly about the presence of hairs (pigmented terminal vs “peach fuzz” hairs), their anatomic location, and any hair removal practices the patient has used. The absence of androgenic alopecia does not exclude underlying hyperandrogenism; however, its presence, especially in younger women, may serve as a clinical marker for underlying hyperandrogenism.5 Some women may camouflage more subtle alopecia through hairstyling, but obtaining this history usually is not problematic, as most women are distressed by any degree of hair loss.

Laboratory Evaluation—A relatively straightforward approach to the workup of androgen excess includes assessment of serum DHEAS, free testosterone, and total testosterone levels.10,30 Elevation of serum DHEAS levels indicates an adrenal source of androgen production. Elevation of testosterone is associated with excess androgens 
produced by the ovaries. Modest elevations of 
DHEAS are most commonly associated with late-onset congenital adrenal hyperplasia that may not have been previously diagnosed. Modest elevation 
of testosterone is most commonly associated with PCOS, which also can be accompanied by an 
elevated luteinizing hormone:follicle-stimulating hormone ratio of 2.5:1 to 3:1.10,30 Marked elevations of DHEAS or testosterone can be indicative of adrenal or ovarian tumors, respectively.30

In some cases, a woman might have 
elevated DHEAS and testosterone levels. A 17-hydroxyprogesterone test can help discriminate between an adrenal or ovarian source of 
androgen excess in these cases, as elevated 
17-hydroxyprogesterone levels indicate that the androgens are coming from the adrenal gland.10,30

It is important that laboratory evaluation be performed when ovulation is not occurring. Blood tests can be drawn just prior to or during menses. It is important that a woman is not taking an oral contraceptive at the time of testing, which can mask an underlying endocrine abnormality.10,11,29,30 Generally, testing can be performed at least 4 to 6 weeks after stopping the oral contraceptive.

 

 

Psychosocial Impact

Facial AV exhibits a broad range of adverse psychological and social effects on many adult females.2,5,13,18 It can be associated with depression, anxiety, psychological stress, and suicidal ideation; therefore, thorough screening for these comorbidities may be warranted in some patients.2,18

Conclusion

The epidemiology, clinical presentation, and clinical and laboratory evaluation of AV in adult females was reviewed in part 1 of this 3-part series. It is important for the clinician to assess the clinical presentation, psychosocial effects, and the possibility of underlying causes of androgen excess. In part 2, skin care 
and topical management of AV in adult females will be discussed.

References

 

1. Perkins AC, Maglione J, Hillebrand GG, et al. 
Acne vulgaris in women: prevalence across the 
life span. J Womens Health (Larchmt). 2012;21: 
223-230.

2. Collier CN, Harper JC, Cafardi JA, et al. The prevalence of acne in adults 20 years and older. J Am Acad Dermatol. 2008;58:56-59.

3. Lucky AW, Biro FM, Huster GA, et al. Acne vulgaris in premenarchal girls. an early sign of puberty associated with rising levels of dehydroepiandrosterone. Arch 
Dermatol. 1994;130:308-314.

4. Mancini AJ, Baldwin HE, Eichenfield LF, et al. Acne life cycle: the spectrum of pediatric disease. Semin Cutan Med Surg. 2011;30(suppl 3):S2-S5.

5. Tanghetti EA, Kawata AK, Daniels SR, et al. Understanding the burden of adult female acne. J Clin Aesthet 
Dermatol. 2014;7:22-30.

6. Goulden V, Stables GI, Cunliffe WJ. Prevalence of facial acne in adults. J Am Acad Dermatol. 1999;41:
577-580.

7. Marks R. Acne and its management beyond the age of 
35 years. Am J Clin Dermatol. 2004;5:459-462.

8. Preneau S, Dreno B. Female acne—a different subtype 
of teenager acne? J Eur Acad Dermatol Venereol. 2012;26:277-282.

9. Kim GK, Del Rosso JQ. Oral spironolactone in post-teenage female patients with acne vulgaris: practical considerations for the clinician based on current data and clinical experience. J Clin Aesthet Dermatol. 2012;5:37-50.

10. Thiboutot D, Chen W. Update and future of hormonal therapy in acne. Dermatology. 2003;206:57-67.

11. Villasenor J, Berson D, Kroshinsky D. Treatment 
guidelines in adult women. In: Shalita AR, 
Del Rosso JQ, Webster GF, eds. Acne Vulgaris. 
London, United Kingdom: Informa Healthcare; 2011:198-207.

12. Del Rosso JQ, Zeichner J. What’s new in the medicine cabinet? a panoramic review of clinically relevant information for the busy dermatologist. J Clin Aesthet Dermatol. 2014;7:26-30.

13. Del Rosso JQ, Kircik L, Gallagher CJ. Comparative efficacy and tolerability of dapsone 5% gel in adult versus adolescent females with acne vulgaris. J Clin Aesthet 
Dermatol. 2015;8:31-37.

14. Dreno B, Layton A, Zouboulis CC, et al. Adult female acne: a new paradigm. J Eur Acad Dermatol Venereol. 2013;27:1063-1070.

15. Choi CW, Lee DH, Kim HS, et al. The clinical features of late onset acne compared with early onset 
acne in women. J Eur Acad Dermatol Venereol. 2011;25:454-461.

16. Dréno B, Thiboutot D, Layton AM, et al; Global 
Alliance to Improve Outcomes in Acne. Large-scale international study enhances understanding of an emerging acne population: adult females. J Eur Acad Dermatol Venereol. 2015;29:1096-1106.

17. Kane A, Niang SO, Diagne AC, et al. Epidemiologic, clinical, and therapeutic features of acne in Dakar, 
Senegal. Int J Dermatol. 2007;46(suppl 1):36-38.

18. Callender VD, Alexis AF, Daniels SR, et al. Racial differences in clinical characteristics, perceptions and behaviors, and psychosocial impact of adult female acne. J Clin Aesthet Dermatol. 2014;7:19-31.

19. Davis SA, Narahari S, Feldman SR, et al. Top dermatologic conditions in patients of color: an analysis of nationally representative data. J Drugs Dermatol. 2012;11:466-473.

20. Rendon MI, Rodriguez DA, Kawata AK, et al. Acne treatment patterns, expectations, and satisfaction among adult females of different races/ethnicities. 
Clin Cosmet Investig Dermatol. 2015;8:231-238.

21. Khunger N, Kumar C. A clinico-epidemiological 
study of adult acne: is it different from adolescent 
acne? Indian J Dermatol Venereol Leprol. 2012;78:
335-341.

22. Alexis AF. Acne vulgaris in skin of color: understanding nuances and optimizing treatment outcomes. J Drugs 
Dermatol. 2014;13(suppl 6):S61-S65.

23. Dall’oglio F, Tedeschi A, Fabbrocini G, et al. Cosmetics for acne: indications and recommendations for an evidence-based approach. G Ital Dermatol Venereol. 2015;150:1-11.

24. Draelos Z. Facial cosmetics for acne patients. In: 
Draelos Z. Cosmetics in Dermatology. 2nd Ed. 
New York, NY: Churchill Livingstone Inc; 1995:15-28.

25. Cunliffe WJ. Acne. London, United Kingdom: Martin Dunitz Ltd; 1989.

26. Simonart T. Acne and whey protein supplementation among bodybuilders. Dermatology. 2012;225:256-258.

27. Silverberg NB. Whey protein precipitating moderate to severe acne flares in 5 teenaged athletes. Cutis. 2012;90:70-72.

28. Bronsnick T, Murzaku EC, Rao BK. Diet in dermatology: part I. atopic dermatitis, acne, and nonmelanoma skin cancer. J Am Acad Dermatol. 2014;71:1039.

29. Keri J, Berson DS, Thiboutot DM. Hormonal treatment of acne in women. In: Shalita AR, Del Rosso J, 
Webster G, eds. Acne Vulgaris. London, United 
Kingdom: Informa Healthcare; 2011:146-155.

30. Thiboutot D. Hormones and acne: pathophysiology, clinical evaluation and therapies. Sem Cutan Med Surg. 2001;20:144-153.

31. Borgia F, Cannavò S, Guarneri F, et al. Correlation between endocrinological parameters and acne 
severity in adult women. Acta Derm Venereol. 2004;84:201-204.

32. Clark CM, Rudolph J, Gerber DA, et al. Dermatologic manifestation of hyperandrogenism: a retrospective chart review. Skinmed. 2014;12:84-88.

33. Zeichner JA. Evaluating and treating the adult 
female patient with acne. J Drugs Dermatol. 2013;12:1416-1427.

Article PDF
media_1b35c69_CT096010236.PDF
Author and Disclosure Information

Dr. Del Rosso is from Touro University College of Osteopathic Medicine, Henderson, Nevada, and Las Vegas Dermatology, Nevada. 
Dr. Harper is in private practice, Birmingham, Alabama. Dr. Graber is in private practice, Boston, Massachusetts. Dr. Thiboutot is from Penn State University Medical Center, Hershey. Dr. Silverberg is from the Department of Dermatology, Mount Sinai St. Luke’s-Roosevelt and Beth Israel Medical Center of the Icahn School of Medicine at Mount Sinai, New York, New York. Drs. D.Z. and L.F. Eichenfield are from the University of California, San Diego School of Medicine. Dr. L.F. Eichenfield also is from Rady Children’s Hospital, San Diego, California.
 Dr. Del Rosso is an advisory board member, consultant, and/or speaker for Allergan, Inc; Aqua Pharmaceuticals; Bayer Health Care Pharmaceuticals; Dermira, Inc; Ferndale Laboratories, Inc; Galderma Laboratories, LP; Mimetica; Promius Pharma; Ranbaxy Laboratories Limited; Sebacia; Suneva Medical, Inc; Unilever; and Valeant Pharmaceuticals International, Inc. He also is a researcher for Allergan, Inc; Ranbaxy Laboratories Limited; Sebacia; and Suneva Medical, Inc. Drs. Harper, Graber, D.Z. Eichenfield, and L.F. Eichenfield report no conflict of interest. Dr. Thiboutot is a consultant for and has received research grants from Allergan, Inc, and Galderma Laboratories, LP. 
Dr. Silverberg has been an investigator for Allergan, Inc, as well as an advisory board member for Galderma Laboratories, LP, and Johnson & Johnson Consumer Inc.


This article is an educational initiative of the American Acne & Rosacea Society (AARS) intended to be a general guide to assist the clinician. The content has been developed solely by the authors. There was no input or contribution from industry or any outside agency related to this publication. The content was reviewed and approved by the authors and Board of Directors of the AARS.
 This article is the first of a 3-part series. The second part will appear next month.


Correspondence: James Q. Del Rosso, DO (jqdelrosso@yahoo.com).

Issue
Cutis - 96(4)
Publications
Cutis
Clinical Guidelines Hub
MDedge Dermatology
Topics
Acne
Page Number
236-241
Legacy Keywords
acne vulgaris, AARS, American Acne & Rosacea Society, acne, female acne, women, acne management
Sections
Drug Therapy
Author(s)
James Q. Del Rosso, DO
Julie C. Harper, MD
Emmy M. Graber, MD, MBA
Diane Thiboutot, MD
Nanette B. Silverberg, MD
Dawn Zhang Eichenfield, PhD
Lawrence F. Eichenfield, MD
Author(s)
James Q. Del Rosso, DO
Julie C. Harper, MD
Emmy M. Graber, MD, MBA
Diane Thiboutot, MD
Nanette B. Silverberg, MD
Dawn Zhang Eichenfield, PhD
Lawrence F. Eichenfield, MD
Author and Disclosure Information

Dr. Del Rosso is from Touro University College of Osteopathic Medicine, Henderson, Nevada, and Las Vegas Dermatology, Nevada. 
Dr. Harper is in private practice, Birmingham, Alabama. Dr. Graber is in private practice, Boston, Massachusetts. Dr. Thiboutot is from Penn State University Medical Center, Hershey. Dr. Silverberg is from the Department of Dermatology, Mount Sinai St. Luke’s-Roosevelt and Beth Israel Medical Center of the Icahn School of Medicine at Mount Sinai, New York, New York. Drs. D.Z. and L.F. Eichenfield are from the University of California, San Diego School of Medicine. Dr. L.F. Eichenfield also is from Rady Children’s Hospital, San Diego, California.
 Dr. Del Rosso is an advisory board member, consultant, and/or speaker for Allergan, Inc; Aqua Pharmaceuticals; Bayer Health Care Pharmaceuticals; Dermira, Inc; Ferndale Laboratories, Inc; Galderma Laboratories, LP; Mimetica; Promius Pharma; Ranbaxy Laboratories Limited; Sebacia; Suneva Medical, Inc; Unilever; and Valeant Pharmaceuticals International, Inc. He also is a researcher for Allergan, Inc; Ranbaxy Laboratories Limited; Sebacia; and Suneva Medical, Inc. Drs. Harper, Graber, D.Z. Eichenfield, and L.F. Eichenfield report no conflict of interest. Dr. Thiboutot is a consultant for and has received research grants from Allergan, Inc, and Galderma Laboratories, LP. 
Dr. Silverberg has been an investigator for Allergan, Inc, as well as an advisory board member for Galderma Laboratories, LP, and Johnson & Johnson Consumer Inc.


This article is an educational initiative of the American Acne & Rosacea Society (AARS) intended to be a general guide to assist the clinician. The content has been developed solely by the authors. There was no input or contribution from industry or any outside agency related to this publication. The content was reviewed and approved by the authors and Board of Directors of the AARS.
 This article is the first of a 3-part series. The second part will appear next month.


Correspondence: James Q. Del Rosso, DO (jqdelrosso@yahoo.com).

Author and Disclosure Information

Dr. Del Rosso is from Touro University College of Osteopathic Medicine, Henderson, Nevada, and Las Vegas Dermatology, Nevada. 
Dr. Harper is in private practice, Birmingham, Alabama. Dr. Graber is in private practice, Boston, Massachusetts. Dr. Thiboutot is from Penn State University Medical Center, Hershey. Dr. Silverberg is from the Department of Dermatology, Mount Sinai St. Luke’s-Roosevelt and Beth Israel Medical Center of the Icahn School of Medicine at Mount Sinai, New York, New York. Drs. D.Z. and L.F. Eichenfield are from the University of California, San Diego School of Medicine. Dr. L.F. Eichenfield also is from Rady Children’s Hospital, San Diego, California.
 Dr. Del Rosso is an advisory board member, consultant, and/or speaker for Allergan, Inc; Aqua Pharmaceuticals; Bayer Health Care Pharmaceuticals; Dermira, Inc; Ferndale Laboratories, Inc; Galderma Laboratories, LP; Mimetica; Promius Pharma; Ranbaxy Laboratories Limited; Sebacia; Suneva Medical, Inc; Unilever; and Valeant Pharmaceuticals International, Inc. He also is a researcher for Allergan, Inc; Ranbaxy Laboratories Limited; Sebacia; and Suneva Medical, Inc. Drs. Harper, Graber, D.Z. Eichenfield, and L.F. Eichenfield report no conflict of interest. Dr. Thiboutot is a consultant for and has received research grants from Allergan, Inc, and Galderma Laboratories, LP. 
Dr. Silverberg has been an investigator for Allergan, Inc, as well as an advisory board member for Galderma Laboratories, LP, and Johnson & Johnson Consumer Inc.


This article is an educational initiative of the American Acne & Rosacea Society (AARS) intended to be a general guide to assist the clinician. The content has been developed solely by the authors. There was no input or contribution from industry or any outside agency related to this publication. The content was reviewed and approved by the authors and Board of Directors of the AARS.
 This article is the first of a 3-part series. The second part will appear next month.


Correspondence: James Q. Del Rosso, DO (jqdelrosso@yahoo.com).

Article PDF
media_1b35c69_CT096010236.PDF
Article PDF
media_1b35c69_CT096010236.PDF
Related Articles
Treating Acne During Pregnancy and Lactation
Acne Scarring: A Review of Cosmetic Therapies

It was not long ago that acne vulgaris (AV) was commonly considered to be a skin disease that affected teenagers with little attention given to preadolescent and postadolescent AV. This perspective has changed, with more attention being given to AV across a broad range of affected 
age groups, including preadolescent, adolescent, and postadolescent subgroups.1-5 Earlier onset of adrenarche has led to earlier development of AV in many young girls, with a higher range of dehydroepiandrosterone sulfate (DHEAS) levels observed overall in those with AV as compared to a normal age-matched population.3,4 At the other end of the age spectrum, AV is a common phenomenon in adult females, with at least half of women estimated to exhibit some form of AV.1,2,5-8 Based on a 
large survey of females and males (N=1013), the prevalence of AV in adult females has been reported to be 50.9%, 35.2%, 26.3%, and 15.3% among women aged 20 to 29 years, 30 to 39 years, 40 to 49 years, and 50 years and older, respectively.2 Acne vulgaris that persists beyond adolescence into adulthood is termed persistent acne, or early-onset acne, and the development of AV in women 25 years and older who have not previously been affected by AV has been termed late-onset acne.6,8,9 Publications on the management of AV in adult women have focused primarily on systemic hormonal therapies; however, topical therapies more recently have received greater attention in this subpopulation9-12 and will be discussed in part 2 of this series. Because data on AV in women are 
limited primarily to involvement of the face and neck region, this article does not address truncal AV unless otherwise specified. Table 1 depicts factors that can influence the management of AV in adult women.

Visible Patterns and Considerations for Clinical Evaluation 


Clinical Patterns

Although epidemiologic and demographic data are limited in the subpopulation of women with AV, it is reported that females account for up to 82% of adults with AV, with approximately 75% presenting with AV that is clinically similar to their disease course in adolescence.2,5,13 Among those women with persistent AV, some state that their AV is worse compared to adolescence, while others report it is not as severe. The pattern of AV often is similar to that seen in adolescence, presenting as mixed comedonal and inflammatory papular/pustular lesions diffusely distributed on the face; in other cases, a more selectively distributed U-shaped pattern is noted, characterized predominantly by inflammatory papules and/or nodules involving the lower cheeks and jawline margin, with lesions also commonly noted on the anterior and lateral neck.5,8,9,13-16 A U-shaped pattern is believed to be more common in late-onset AV, often with persistence into the mid-40s.1,15,17 It is important to emphasize the need for additional studies on the demographics and clinical characteristics of AV in adult females, especially correlations between onset, age, and clinical patterns of AV.

An international, prospective, observational study assessed the clinical characteristics of AV in adults (aged ≥25 years) at a dermatology visit for acne (N=374).16 Participants who were under management for their AV showed severity grades of mild (clear/almost clear) in 47.3% of cases. Involvement of multiple facial sites—cheeks, forehead, mandibular region, and temples—was noted in 89.8% of women, often with both inflammatory and comedonal lesions, which is a pattern similar to adolescent AV. Inflammatory lesions alone were observed in 6.4% of women, 17.1% had comedonal AV only, 
and truncal AV was present in 48.4%.16 Additional well-designed studies are needed to determine if this study reflects an accurate qualitative and 
quantitative depiction of the spectrum of AV in adult females.

Mandibular Pattern

In the observational study of AV in adults, AV localized to the mandibular area was noted in only 11.2% of participants.16 Women with localized mandibular AV were more likely than women without localized AV to be employed, noted greater daily stress levels, and tended to report more psychologically stressful jobs. Interestingly, the subgroup with mandibular acne alone was much less likely 
to exhibit a global severity grade of moderate or higher (7.1% vs 50.1%), truncal acne 
(19.0% vs 51.9%), postinflammatory hyperpigmentation (23.8% vs 51.9%), and erythema (19.0% vs 48.4%), suggesting a unique subset of AV presentation.16

Ethnicity/Skin Color

Women of all ethnicities and skin types may be affected by AV.1,18-20 Earlier age of onset of AV has been suggested in white women; however, earlier onset of adrenarche may be more frequent in black girls, which supports an earlier age of onset of AV in this subpopulation.15-17 Women with skin of color usually express greater concern with persistent dyschromia at sites where lesions have resolved, and presence of acne scars is a concern among women regardless of skin color, ethnicity, or race.18,20-22

 

 

Scarring

Acne scarring has been noted to affect up to 
three-fourths of adult women in one report17 and 
often is stated by patients to be a cause of concern 
and frustration.1,5,17

Perimenstrual Flaring

Flaring associated with menses is commonly reported in adult females with AV, with 56%, 17%, and 
3% of women in one study (n=230) reporting worsening before, during, or after menses, respectively.21

External Factors

Comedogenic products used for skin care, cover-up makeup, or hair care may be important to consider in selected cases as potential etiologic or exacerbating factors in adult females with AV; they also may be used in the management of AV.23-25 Adult females often are perplexed and frustrated by the presence of AV after their 
teenaged years and anxiously wonder about or search for the potential causes. Many women use cosmetic products to cover up facial AV.5,23-25 Therefore, even if skin care or personal hygiene products or makeup are not believed to be an etiologic factor, many patients appreciate that their dermatologist addressed skin care and cosmetics as a component of AV management and provided appropriate recommendations.5,13

Ingestion of dietary supplements containing whey protein have been associated with precipitation of AV.26,27 Diets with specific content characteristics have been implicated as potential etiologic or exacerbating factors for AV; however, data are limited and specific recommendations remain elusive at present. Individual cases may warrant consideration of dietary factors, especially when treatment resistance is noted.28 Importantly, progestin-only contraceptives (ie, injectables, intrauterine devices) also can exacerbate or induce AV.29

Hyperandrogenism

Although most adult females with AV are reported to have normal serum androgen levels when tested, it is important to explore potential signs and symptoms that are suggestive of underlying hyperandrogenism through both the patient’s history and physical examination.9-11,21,29-33 Some investigators have suggested that underlying peripheral hyperandrogenism is the leading cause of AV in adult females, 
with or without concurrent polycystic ovarian syndrome (PCOS), though it is believed that most women with AV exhibit normal results when 
undergoing laboratory testing for androgen excess.10,11,21,29,30 Nevertheless, it is important to consider the possibility of underlying causes of androgen excess (Table 2), the most common being PCOS and late-onset congenital adrenal hyperplasia; an androgen-secreting tumor is less common.11,29-33 It is suggested that screening for underlying endocrinopathy should be conducted in women presenting with (1) AV recalcitrant to conventional treatment, (2) sudden emergence of severe AV, 
(3) concurrent signs/symptoms of androgen 
excess, and/or (4) AV relapse shortly after isotretinoin therapy.7,11,16,33

Hirsutism and acanthosis nigricans have been reported to be more reliable predictors of hyperandrogenism than androgenic alopecia.21 Although it may be subtle in some cases, acanthosis nigricans is harder to camouflage, so the clinician can usually detect it if a thorough physical examination is performed. However, a patient may not voluntarily report to the clinician and their staff that she has hair removed, so despite a thorough examination, the clinician may not detect hirsutism. Therefore, it is important to inquire directly about the presence of hairs (pigmented terminal vs “peach fuzz” hairs), their anatomic location, and any hair removal practices the patient has used. The absence of androgenic alopecia does not exclude underlying hyperandrogenism; however, its presence, especially in younger women, may serve as a clinical marker for underlying hyperandrogenism.5 Some women may camouflage more subtle alopecia through hairstyling, but obtaining this history usually is not problematic, as most women are distressed by any degree of hair loss.

Laboratory Evaluation—A relatively straightforward approach to the workup of androgen excess includes assessment of serum DHEAS, free testosterone, and total testosterone levels.10,30 Elevation of serum DHEAS levels indicates an adrenal source of androgen production. Elevation of testosterone is associated with excess androgens 
produced by the ovaries. Modest elevations of 
DHEAS are most commonly associated with late-onset congenital adrenal hyperplasia that may not have been previously diagnosed. Modest elevation 
of testosterone is most commonly associated with PCOS, which also can be accompanied by an 
elevated luteinizing hormone:follicle-stimulating hormone ratio of 2.5:1 to 3:1.10,30 Marked elevations of DHEAS or testosterone can be indicative of adrenal or ovarian tumors, respectively.30

In some cases, a woman might have 
elevated DHEAS and testosterone levels. A 17-hydroxyprogesterone test can help discriminate between an adrenal or ovarian source of 
androgen excess in these cases, as elevated 
17-hydroxyprogesterone levels indicate that the androgens are coming from the adrenal gland.10,30

It is important that laboratory evaluation be performed when ovulation is not occurring. Blood tests can be drawn just prior to or during menses. It is important that a woman is not taking an oral contraceptive at the time of testing, which can mask an underlying endocrine abnormality.10,11,29,30 Generally, testing can be performed at least 4 to 6 weeks after stopping the oral contraceptive.

 

 

Psychosocial Impact

Facial AV exhibits a broad range of adverse psychological and social effects on many adult females.2,5,13,18 It can be associated with depression, anxiety, psychological stress, and suicidal ideation; therefore, thorough screening for these comorbidities may be warranted in some patients.2,18

Conclusion

The epidemiology, clinical presentation, and clinical and laboratory evaluation of AV in adult females was reviewed in part 1 of this 3-part series. It is important for the clinician to assess the clinical presentation, psychosocial effects, and the possibility of underlying causes of androgen excess. In part 2, skin care 
and topical management of AV in adult females will be discussed.

It was not long ago that acne vulgaris (AV) was commonly considered to be a skin disease that affected teenagers with little attention given to preadolescent and postadolescent AV. This perspective has changed, with more attention being given to AV across a broad range of affected 
age groups, including preadolescent, adolescent, and postadolescent subgroups.1-5 Earlier onset of adrenarche has led to earlier development of AV in many young girls, with a higher range of dehydroepiandrosterone sulfate (DHEAS) levels observed overall in those with AV as compared to a normal age-matched population.3,4 At the other end of the age spectrum, AV is a common phenomenon in adult females, with at least half of women estimated to exhibit some form of AV.1,2,5-8 Based on a 
large survey of females and males (N=1013), the prevalence of AV in adult females has been reported to be 50.9%, 35.2%, 26.3%, and 15.3% among women aged 20 to 29 years, 30 to 39 years, 40 to 49 years, and 50 years and older, respectively.2 Acne vulgaris that persists beyond adolescence into adulthood is termed persistent acne, or early-onset acne, and the development of AV in women 25 years and older who have not previously been affected by AV has been termed late-onset acne.6,8,9 Publications on the management of AV in adult women have focused primarily on systemic hormonal therapies; however, topical therapies more recently have received greater attention in this subpopulation9-12 and will be discussed in part 2 of this series. Because data on AV in women are 
limited primarily to involvement of the face and neck region, this article does not address truncal AV unless otherwise specified. Table 1 depicts factors that can influence the management of AV in adult women.

Visible Patterns and Considerations for Clinical Evaluation 


Clinical Patterns

Although epidemiologic and demographic data are limited in the subpopulation of women with AV, it is reported that females account for up to 82% of adults with AV, with approximately 75% presenting with AV that is clinically similar to their disease course in adolescence.2,5,13 Among those women with persistent AV, some state that their AV is worse compared to adolescence, while others report it is not as severe. The pattern of AV often is similar to that seen in adolescence, presenting as mixed comedonal and inflammatory papular/pustular lesions diffusely distributed on the face; in other cases, a more selectively distributed U-shaped pattern is noted, characterized predominantly by inflammatory papules and/or nodules involving the lower cheeks and jawline margin, with lesions also commonly noted on the anterior and lateral neck.5,8,9,13-16 A U-shaped pattern is believed to be more common in late-onset AV, often with persistence into the mid-40s.1,15,17 It is important to emphasize the need for additional studies on the demographics and clinical characteristics of AV in adult females, especially correlations between onset, age, and clinical patterns of AV.

An international, prospective, observational study assessed the clinical characteristics of AV in adults (aged ≥25 years) at a dermatology visit for acne (N=374).16 Participants who were under management for their AV showed severity grades of mild (clear/almost clear) in 47.3% of cases. Involvement of multiple facial sites—cheeks, forehead, mandibular region, and temples—was noted in 89.8% of women, often with both inflammatory and comedonal lesions, which is a pattern similar to adolescent AV. Inflammatory lesions alone were observed in 6.4% of women, 17.1% had comedonal AV only, 
and truncal AV was present in 48.4%.16 Additional well-designed studies are needed to determine if this study reflects an accurate qualitative and 
quantitative depiction of the spectrum of AV in adult females.

Mandibular Pattern

In the observational study of AV in adults, AV localized to the mandibular area was noted in only 11.2% of participants.16 Women with localized mandibular AV were more likely than women without localized AV to be employed, noted greater daily stress levels, and tended to report more psychologically stressful jobs. Interestingly, the subgroup with mandibular acne alone was much less likely 
to exhibit a global severity grade of moderate or higher (7.1% vs 50.1%), truncal acne 
(19.0% vs 51.9%), postinflammatory hyperpigmentation (23.8% vs 51.9%), and erythema (19.0% vs 48.4%), suggesting a unique subset of AV presentation.16

Ethnicity/Skin Color

Women of all ethnicities and skin types may be affected by AV.1,18-20 Earlier age of onset of AV has been suggested in white women; however, earlier onset of adrenarche may be more frequent in black girls, which supports an earlier age of onset of AV in this subpopulation.15-17 Women with skin of color usually express greater concern with persistent dyschromia at sites where lesions have resolved, and presence of acne scars is a concern among women regardless of skin color, ethnicity, or race.18,20-22

 

 

Scarring

Acne scarring has been noted to affect up to 
three-fourths of adult women in one report17 and 
often is stated by patients to be a cause of concern 
and frustration.1,5,17

Perimenstrual Flaring

Flaring associated with menses is commonly reported in adult females with AV, with 56%, 17%, and 
3% of women in one study (n=230) reporting worsening before, during, or after menses, respectively.21

External Factors

Comedogenic products used for skin care, cover-up makeup, or hair care may be important to consider in selected cases as potential etiologic or exacerbating factors in adult females with AV; they also may be used in the management of AV.23-25 Adult females often are perplexed and frustrated by the presence of AV after their 
teenaged years and anxiously wonder about or search for the potential causes. Many women use cosmetic products to cover up facial AV.5,23-25 Therefore, even if skin care or personal hygiene products or makeup are not believed to be an etiologic factor, many patients appreciate that their dermatologist addressed skin care and cosmetics as a component of AV management and provided appropriate recommendations.5,13

Ingestion of dietary supplements containing whey protein have been associated with precipitation of AV.26,27 Diets with specific content characteristics have been implicated as potential etiologic or exacerbating factors for AV; however, data are limited and specific recommendations remain elusive at present. Individual cases may warrant consideration of dietary factors, especially when treatment resistance is noted.28 Importantly, progestin-only contraceptives (ie, injectables, intrauterine devices) also can exacerbate or induce AV.29

Hyperandrogenism

Although most adult females with AV are reported to have normal serum androgen levels when tested, it is important to explore potential signs and symptoms that are suggestive of underlying hyperandrogenism through both the patient’s history and physical examination.9-11,21,29-33 Some investigators have suggested that underlying peripheral hyperandrogenism is the leading cause of AV in adult females, 
with or without concurrent polycystic ovarian syndrome (PCOS), though it is believed that most women with AV exhibit normal results when 
undergoing laboratory testing for androgen excess.10,11,21,29,30 Nevertheless, it is important to consider the possibility of underlying causes of androgen excess (Table 2), the most common being PCOS and late-onset congenital adrenal hyperplasia; an androgen-secreting tumor is less common.11,29-33 It is suggested that screening for underlying endocrinopathy should be conducted in women presenting with (1) AV recalcitrant to conventional treatment, (2) sudden emergence of severe AV, 
(3) concurrent signs/symptoms of androgen 
excess, and/or (4) AV relapse shortly after isotretinoin therapy.7,11,16,33

Hirsutism and acanthosis nigricans have been reported to be more reliable predictors of hyperandrogenism than androgenic alopecia.21 Although it may be subtle in some cases, acanthosis nigricans is harder to camouflage, so the clinician can usually detect it if a thorough physical examination is performed. However, a patient may not voluntarily report to the clinician and their staff that she has hair removed, so despite a thorough examination, the clinician may not detect hirsutism. Therefore, it is important to inquire directly about the presence of hairs (pigmented terminal vs “peach fuzz” hairs), their anatomic location, and any hair removal practices the patient has used. The absence of androgenic alopecia does not exclude underlying hyperandrogenism; however, its presence, especially in younger women, may serve as a clinical marker for underlying hyperandrogenism.5 Some women may camouflage more subtle alopecia through hairstyling, but obtaining this history usually is not problematic, as most women are distressed by any degree of hair loss.

Laboratory Evaluation—A relatively straightforward approach to the workup of androgen excess includes assessment of serum DHEAS, free testosterone, and total testosterone levels.10,30 Elevation of serum DHEAS levels indicates an adrenal source of androgen production. Elevation of testosterone is associated with excess androgens 
produced by the ovaries. Modest elevations of 
DHEAS are most commonly associated with late-onset congenital adrenal hyperplasia that may not have been previously diagnosed. Modest elevation 
of testosterone is most commonly associated with PCOS, which also can be accompanied by an 
elevated luteinizing hormone:follicle-stimulating hormone ratio of 2.5:1 to 3:1.10,30 Marked elevations of DHEAS or testosterone can be indicative of adrenal or ovarian tumors, respectively.30

In some cases, a woman might have 
elevated DHEAS and testosterone levels. A 17-hydroxyprogesterone test can help discriminate between an adrenal or ovarian source of 
androgen excess in these cases, as elevated 
17-hydroxyprogesterone levels indicate that the androgens are coming from the adrenal gland.10,30

It is important that laboratory evaluation be performed when ovulation is not occurring. Blood tests can be drawn just prior to or during menses. It is important that a woman is not taking an oral contraceptive at the time of testing, which can mask an underlying endocrine abnormality.10,11,29,30 Generally, testing can be performed at least 4 to 6 weeks after stopping the oral contraceptive.

 

 

Psychosocial Impact

Facial AV exhibits a broad range of adverse psychological and social effects on many adult females.2,5,13,18 It can be associated with depression, anxiety, psychological stress, and suicidal ideation; therefore, thorough screening for these comorbidities may be warranted in some patients.2,18

Conclusion

The epidemiology, clinical presentation, and clinical and laboratory evaluation of AV in adult females was reviewed in part 1 of this 3-part series. It is important for the clinician to assess the clinical presentation, psychosocial effects, and the possibility of underlying causes of androgen excess. In part 2, skin care 
and topical management of AV in adult females will be discussed.

References

 

1. Perkins AC, Maglione J, Hillebrand GG, et al. 
Acne vulgaris in women: prevalence across the 
life span. J Womens Health (Larchmt). 2012;21: 
223-230.

2. Collier CN, Harper JC, Cafardi JA, et al. The prevalence of acne in adults 20 years and older. J Am Acad Dermatol. 2008;58:56-59.

3. Lucky AW, Biro FM, Huster GA, et al. Acne vulgaris in premenarchal girls. an early sign of puberty associated with rising levels of dehydroepiandrosterone. Arch 
Dermatol. 1994;130:308-314.

4. Mancini AJ, Baldwin HE, Eichenfield LF, et al. Acne life cycle: the spectrum of pediatric disease. Semin Cutan Med Surg. 2011;30(suppl 3):S2-S5.

5. Tanghetti EA, Kawata AK, Daniels SR, et al. Understanding the burden of adult female acne. J Clin Aesthet 
Dermatol. 2014;7:22-30.

6. Goulden V, Stables GI, Cunliffe WJ. Prevalence of facial acne in adults. J Am Acad Dermatol. 1999;41:
577-580.

7. Marks R. Acne and its management beyond the age of 
35 years. Am J Clin Dermatol. 2004;5:459-462.

8. Preneau S, Dreno B. Female acne—a different subtype 
of teenager acne? J Eur Acad Dermatol Venereol. 2012;26:277-282.

9. Kim GK, Del Rosso JQ. Oral spironolactone in post-teenage female patients with acne vulgaris: practical considerations for the clinician based on current data and clinical experience. J Clin Aesthet Dermatol. 2012;5:37-50.

10. Thiboutot D, Chen W. Update and future of hormonal therapy in acne. Dermatology. 2003;206:57-67.

11. Villasenor J, Berson D, Kroshinsky D. Treatment 
guidelines in adult women. In: Shalita AR, 
Del Rosso JQ, Webster GF, eds. Acne Vulgaris. 
London, United Kingdom: Informa Healthcare; 2011:198-207.

12. Del Rosso JQ, Zeichner J. What’s new in the medicine cabinet? a panoramic review of clinically relevant information for the busy dermatologist. J Clin Aesthet Dermatol. 2014;7:26-30.

13. Del Rosso JQ, Kircik L, Gallagher CJ. Comparative efficacy and tolerability of dapsone 5% gel in adult versus adolescent females with acne vulgaris. J Clin Aesthet 
Dermatol. 2015;8:31-37.

14. Dreno B, Layton A, Zouboulis CC, et al. Adult female acne: a new paradigm. J Eur Acad Dermatol Venereol. 2013;27:1063-1070.

15. Choi CW, Lee DH, Kim HS, et al. The clinical features of late onset acne compared with early onset 
acne in women. J Eur Acad Dermatol Venereol. 2011;25:454-461.

16. Dréno B, Thiboutot D, Layton AM, et al; Global 
Alliance to Improve Outcomes in Acne. Large-scale international study enhances understanding of an emerging acne population: adult females. J Eur Acad Dermatol Venereol. 2015;29:1096-1106.

17. Kane A, Niang SO, Diagne AC, et al. Epidemiologic, clinical, and therapeutic features of acne in Dakar, 
Senegal. Int J Dermatol. 2007;46(suppl 1):36-38.

18. Callender VD, Alexis AF, Daniels SR, et al. Racial differences in clinical characteristics, perceptions and behaviors, and psychosocial impact of adult female acne. J Clin Aesthet Dermatol. 2014;7:19-31.

19. Davis SA, Narahari S, Feldman SR, et al. Top dermatologic conditions in patients of color: an analysis of nationally representative data. J Drugs Dermatol. 2012;11:466-473.

20. Rendon MI, Rodriguez DA, Kawata AK, et al. Acne treatment patterns, expectations, and satisfaction among adult females of different races/ethnicities. 
Clin Cosmet Investig Dermatol. 2015;8:231-238.

21. Khunger N, Kumar C. A clinico-epidemiological 
study of adult acne: is it different from adolescent 
acne? Indian J Dermatol Venereol Leprol. 2012;78:
335-341.

22. Alexis AF. Acne vulgaris in skin of color: understanding nuances and optimizing treatment outcomes. J Drugs 
Dermatol. 2014;13(suppl 6):S61-S65.

23. Dall’oglio F, Tedeschi A, Fabbrocini G, et al. Cosmetics for acne: indications and recommendations for an evidence-based approach. G Ital Dermatol Venereol. 2015;150:1-11.

24. Draelos Z. Facial cosmetics for acne patients. In: 
Draelos Z. Cosmetics in Dermatology. 2nd Ed. 
New York, NY: Churchill Livingstone Inc; 1995:15-28.

25. Cunliffe WJ. Acne. London, United Kingdom: Martin Dunitz Ltd; 1989.

26. Simonart T. Acne and whey protein supplementation among bodybuilders. Dermatology. 2012;225:256-258.

27. Silverberg NB. Whey protein precipitating moderate to severe acne flares in 5 teenaged athletes. Cutis. 2012;90:70-72.

28. Bronsnick T, Murzaku EC, Rao BK. Diet in dermatology: part I. atopic dermatitis, acne, and nonmelanoma skin cancer. J Am Acad Dermatol. 2014;71:1039.

29. Keri J, Berson DS, Thiboutot DM. Hormonal treatment of acne in women. In: Shalita AR, Del Rosso J, 
Webster G, eds. Acne Vulgaris. London, United 
Kingdom: Informa Healthcare; 2011:146-155.

30. Thiboutot D. Hormones and acne: pathophysiology, clinical evaluation and therapies. Sem Cutan Med Surg. 2001;20:144-153.

31. Borgia F, Cannavò S, Guarneri F, et al. Correlation between endocrinological parameters and acne 
severity in adult women. Acta Derm Venereol. 2004;84:201-204.

32. Clark CM, Rudolph J, Gerber DA, et al. Dermatologic manifestation of hyperandrogenism: a retrospective chart review. Skinmed. 2014;12:84-88.

33. Zeichner JA. Evaluating and treating the adult 
female patient with acne. J Drugs Dermatol. 2013;12:1416-1427.

References

 

1. Perkins AC, Maglione J, Hillebrand GG, et al. 
Acne vulgaris in women: prevalence across the 
life span. J Womens Health (Larchmt). 2012;21: 
223-230.

2. Collier CN, Harper JC, Cafardi JA, et al. The prevalence of acne in adults 20 years and older. J Am Acad Dermatol. 2008;58:56-59.

3. Lucky AW, Biro FM, Huster GA, et al. Acne vulgaris in premenarchal girls. an early sign of puberty associated with rising levels of dehydroepiandrosterone. Arch 
Dermatol. 1994;130:308-314.

4. Mancini AJ, Baldwin HE, Eichenfield LF, et al. Acne life cycle: the spectrum of pediatric disease. Semin Cutan Med Surg. 2011;30(suppl 3):S2-S5.

5. Tanghetti EA, Kawata AK, Daniels SR, et al. Understanding the burden of adult female acne. J Clin Aesthet 
Dermatol. 2014;7:22-30.

6. Goulden V, Stables GI, Cunliffe WJ. Prevalence of facial acne in adults. J Am Acad Dermatol. 1999;41:
577-580.

7. Marks R. Acne and its management beyond the age of 
35 years. Am J Clin Dermatol. 2004;5:459-462.

8. Preneau S, Dreno B. Female acne—a different subtype 
of teenager acne? J Eur Acad Dermatol Venereol. 2012;26:277-282.

9. Kim GK, Del Rosso JQ. Oral spironolactone in post-teenage female patients with acne vulgaris: practical considerations for the clinician based on current data and clinical experience. J Clin Aesthet Dermatol. 2012;5:37-50.

10. Thiboutot D, Chen W. Update and future of hormonal therapy in acne. Dermatology. 2003;206:57-67.

11. Villasenor J, Berson D, Kroshinsky D. Treatment 
guidelines in adult women. In: Shalita AR, 
Del Rosso JQ, Webster GF, eds. Acne Vulgaris. 
London, United Kingdom: Informa Healthcare; 2011:198-207.

12. Del Rosso JQ, Zeichner J. What’s new in the medicine cabinet? a panoramic review of clinically relevant information for the busy dermatologist. J Clin Aesthet Dermatol. 2014;7:26-30.

13. Del Rosso JQ, Kircik L, Gallagher CJ. Comparative efficacy and tolerability of dapsone 5% gel in adult versus adolescent females with acne vulgaris. J Clin Aesthet 
Dermatol. 2015;8:31-37.

14. Dreno B, Layton A, Zouboulis CC, et al. Adult female acne: a new paradigm. J Eur Acad Dermatol Venereol. 2013;27:1063-1070.

15. Choi CW, Lee DH, Kim HS, et al. The clinical features of late onset acne compared with early onset 
acne in women. J Eur Acad Dermatol Venereol. 2011;25:454-461.

16. Dréno B, Thiboutot D, Layton AM, et al; Global 
Alliance to Improve Outcomes in Acne. Large-scale international study enhances understanding of an emerging acne population: adult females. J Eur Acad Dermatol Venereol. 2015;29:1096-1106.

17. Kane A, Niang SO, Diagne AC, et al. Epidemiologic, clinical, and therapeutic features of acne in Dakar, 
Senegal. Int J Dermatol. 2007;46(suppl 1):36-38.

18. Callender VD, Alexis AF, Daniels SR, et al. Racial differences in clinical characteristics, perceptions and behaviors, and psychosocial impact of adult female acne. J Clin Aesthet Dermatol. 2014;7:19-31.

19. Davis SA, Narahari S, Feldman SR, et al. Top dermatologic conditions in patients of color: an analysis of nationally representative data. J Drugs Dermatol. 2012;11:466-473.

20. Rendon MI, Rodriguez DA, Kawata AK, et al. Acne treatment patterns, expectations, and satisfaction among adult females of different races/ethnicities. 
Clin Cosmet Investig Dermatol. 2015;8:231-238.

21. Khunger N, Kumar C. A clinico-epidemiological 
study of adult acne: is it different from adolescent 
acne? Indian J Dermatol Venereol Leprol. 2012;78:
335-341.

22. Alexis AF. Acne vulgaris in skin of color: understanding nuances and optimizing treatment outcomes. J Drugs 
Dermatol. 2014;13(suppl 6):S61-S65.

23. Dall’oglio F, Tedeschi A, Fabbrocini G, et al. Cosmetics for acne: indications and recommendations for an evidence-based approach. G Ital Dermatol Venereol. 2015;150:1-11.

24. Draelos Z. Facial cosmetics for acne patients. In: 
Draelos Z. Cosmetics in Dermatology. 2nd Ed. 
New York, NY: Churchill Livingstone Inc; 1995:15-28.

25. Cunliffe WJ. Acne. London, United Kingdom: Martin Dunitz Ltd; 1989.

26. Simonart T. Acne and whey protein supplementation among bodybuilders. Dermatology. 2012;225:256-258.

27. Silverberg NB. Whey protein precipitating moderate to severe acne flares in 5 teenaged athletes. Cutis. 2012;90:70-72.

28. Bronsnick T, Murzaku EC, Rao BK. Diet in dermatology: part I. atopic dermatitis, acne, and nonmelanoma skin cancer. J Am Acad Dermatol. 2014;71:1039.

29. Keri J, Berson DS, Thiboutot DM. Hormonal treatment of acne in women. In: Shalita AR, Del Rosso J, 
Webster G, eds. Acne Vulgaris. London, United 
Kingdom: Informa Healthcare; 2011:146-155.

30. Thiboutot D. Hormones and acne: pathophysiology, clinical evaluation and therapies. Sem Cutan Med Surg. 2001;20:144-153.

31. Borgia F, Cannavò S, Guarneri F, et al. Correlation between endocrinological parameters and acne 
severity in adult women. Acta Derm Venereol. 2004;84:201-204.

32. Clark CM, Rudolph J, Gerber DA, et al. Dermatologic manifestation of hyperandrogenism: a retrospective chart review. Skinmed. 2014;12:84-88.

33. Zeichner JA. Evaluating and treating the adult 
female patient with acne. J Drugs Dermatol. 2013;12:1416-1427.

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Status Report From the American Acne & Rosacea Society on Medical Management of Acne in Adult Women, Part 1: Overview, Clinical Characteristics, and Laboratory Evaluation
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Status Report From the American Acne & Rosacea Society on Medical Management of Acne in Adult Women, Part 1: Overview, Clinical Characteristics, and Laboratory Evaluation
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Practice Points

  • Acne in adult women is common and may persist beyond the adolescent years or may be late in 
onset with emergence usually during the early to mid-20s.
  • Adult women with acne often are frustrated, as they perceive it as a disorder of teenagers and are perplexed by its presence later in life. They often are distressed by unpredictable flares as well as difficulty with covering lesions and associated dyschromia and scarring.
  • Clinical patterns of acne in adult women are mixed inflammatory and comedonal facial acne or a U-shaped pattern of inflammatory lesions involving the lower face and neck.
  • Laboratory testing is not considered mandatory in all cases. The clinician is encouraged to carefully evaluate each case and determine if further evaluation to detect a cause of androgen excess is warranted.
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Epithelioid Sarcoma Resembling Benign Fibrous Histiocytoma

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Epithelioid Sarcoma Resembling Benign Fibrous Histiocytoma
Author(s)
Michael C. Lynch, MD
Emmy M. Graber, MD, MBA
T. Shane Johnson, MD

Epithelioid sarcoma (ES) is a rare malignant soft tissue neoplasm that is most often encountered on the distal extremities of young adults.1 Epithelioid sarcoma is notorious for its tendency to mimic palisading granulomatous processes such as granuloma annulare. We report a case of ES on the right hand of a 23-year-old man that resembled a benign fibrous histiocytoma (dermatofibroma) on incisional biopsy. The typical histopathologic features of ES were identified after amputation of the hand and evaluation of the deeper regions of the tumor. The tendency for ES to mimic granulomatous processes is a common diagnostic pitfall, but the potential for its close resemblance to benign fibrous histiocytoma is less recognized.

 

Figure 1. A 0.8×0.6-cm ulcerated nodule on the hypothenar region of the right hand (A). Four months after initial presentation the nodule measured 1.4×1 cm (B).

Case Report

A 23-year-old man presented with a nonhealing lesion on the right palm. His medical history was remarkable for a giant cell tumor of the tendon sheath involving the right fifth finger that had been treated via excision at an outside institution 2 years prior. Clinical examination revealed a 0.8×0.6-cm painful, firm, ulcerated dermal nodule with a hemorrhagic crust on the palmar surface of the right hand (Figure 1A). The clinical differential diagnosis included melanoma, traumatized verruca vulgaris, thrombosed pyogenic granuloma, and foreign body. A shave biopsy demonstrated verrucous epidermal hyperplasia, but the specimen did not include the dermis. Cultures of the lesion were positive for Staphylococcus aureus, and antibiotic therapy was initiated. In light of the clinical findings and the patient’s history of a giant cell tumor, imaging studies were performed. Magnetic resonance angiography showed abnormal masslike infiltrative enhancement throughout the soft tissues surrounding the right fifth metacarpal bone. The differential included a recurrent giant cell tumor, fibromatosis, and other soft tissue neoplasms.

After several missed appointments and surgery cancellations, the patient returned 4 months later for an incisional biopsy. Physical examination revealed a persistent palmar ulcer that had grown to 1.4×1 cm in size, along with an indurated purple plaque wrapping around the ulnar aspect of the right hand (Figure 1B). The biopsy demonstrated a proliferation of spindled and ovoid cells with scant cytoplasm that surrounded sclerotic collagen bundles resembling a dermatofibroma (Figure 2A). Cytologic atypia and mitotic activity were absent (Figure 2B). Glass slides of the original biopsy, which ultimately led to the diagnosis of the giant cell tumor of the tendon sheath more than 2 years earlier, were obtained and showed similar features. The proliferating cells were strongly and diffusely immunoreactive for vimentin, CD34, and cancer antigen 125 (CA 125). Scattered tumor cells strongly expressed cytokeratins (CKs) AE1/AE3 and cell adhesion molecule 5.2 (Figure 3). Staining for CD99 and epithelial membrane antigen was diffuse but weak. Factor XIIIa, S-100, CK7, smooth muscle actin, muscle-specific actin (HHF35), CD31, CD68, and B-cell lymphoma 2 were negative within the proliferating cells. Based on the clinical examination and results of the immunohistochemical staining, a diagnosis of ES was favored.

 

Figure 2. Low-power view of an incisional biopsy resembled a fibrohistiocytomalike neoplasm, as the tumor was composed of plump spindle cells that trapped sclerotic collagen bundles (A)(H&E, original magnification ×40). The tumor lacked significant cytologic atypia and mitotic figures were not seen (B)(H&E, original magnification ×200).

 

After a negative metastatic workup, amputation of the right hand was performed. The amputation specimen showed a tumor that extended through the entire hand with encasement of large vessels and tendons. Although the more superficial regions were cytologically bland, deep-seated regions of the tumor exhibited greater cellularity, nuclear pleomorphism, and mitotic activity (Figure 4). There was no bone involvement. Right axillary sentinel lymph nodes were negative for metastasis. Eighteen months later the patient developed chest and back pain with dyspnea. Thorascopic surgery was performed for a left pleural effusion and metastases to the left parietal pleura and adjacent soft tissue were identified. The patient was subsequently lost to follow-up.

Comment

First described by Enzinger1 in 1970, ES is a rare malignant soft tissue neoplasm that most frequently arises on the hands, forearms, and pretibial soft tissues of young adults.1-3 It is an aggressive tumor characterized by frequent recurrences and a high metastatic rate, with lung and regional lymph nodes being favored metastatic sites.1-5 Periods of several months or even years often pass between the initial presentation and establishment of a correct diagnosis, as ES frequently is mistaken for other benign conditions. The tendency for ES to mimic granulomatous processes is a common diagnostic pitfall, but the potential for its close resemblance to benign fibrous histiocytoma is less recognized.6,7 In his original series of 62 cases, Enzinger1 noted that 17 patients were referred for treatment with a diagnosis of a benign fibrohistiocytic neoplasm, and other reports have described a resemblance to fibrous and fibrohistiocytic neoplasms.8-11 Mirra et al10 designated these tumors as fibromalike variants of ES. Additional subtypes of ES have subsequently been recognized, including those described as angiomatoid or angiosarcomalike, reflecting the potential of ES to resemble vascular tumors.12 A proximal type of ES also has been described. This lesion presents as a deep-seated tumor on the proximal limbs and is associated with more aggressive behavior. It lacks the granulomalike pattern and has more prominent epithelioid and rhabdoid histological presentation.13-15

 

 

Epithelioid sarcoma is a mesenchymal tumor that can display multidirectional differentiation that is primarily epithelial.16 The precise histogenesis of ES remains unclear, but studies have demonstrated a spectrum of differentiation that ranges from primitive myofibroblast or fibrohistiocytelike cells to those with well-developed epithelial properties.16,17 Epithelioid sarcoma characteristically coexpresses vimentin and low-molecular-weight CKs such as cell adhesion molecule 5.2. The tumor cells often are immunoreactive for epithelial membrane antigen and more than 50% of cases exhibit remarkable CD34 positivity.16 More recent studies have further refined the immunophenotype, demonstrating frequent expression of CK8 and CK19 but less commonly CK7, CK20, CK34bE12, and CK5/6.18-20 Additional studies reported that in 10 of 11 cases, ES was positive for CA 125 on immunohistochemical staining, and 3 of 5 patients also had elevated serum CA 125 levels.21,22 More recently, Hoshino et al23 showed elevated serum CA 125 levels in 5 of 7 patients with ES. Cancer antigen 125 is a high-molecular-weight glycoprotein commonly used in the identification of epithelial ovarian carcinomas; however, it also has been described in a number of other neoplasms including carcinomas of the breast, lungs, and colon and lymphoma.24-27 Although it appears that the addition of CA 125 to a panel of other immunohistochemical stains may be helpful in differentiating ES from other soft tissue sarcomas and serum CA 125 levels may help determine tumor burden, currently the number of cases studied is too small to definitively make that conclusion.21,23 In our case, the tumor cells were strongly and diffusely positive for CA 125. Serum CA 125 levels were not available.

 

Figure 3. Tumor cells focally showed strong membranous staining for cytokeratin AE1/AE3 (original magnification ×400).
Figure 3. Tumor cells focally showed strong membranous staining for cytokeratin AE1/AE3 (original magnification ×400).

 

 

Figure 4. High-power view of the tumor from the amputation specimen showed sheets of epithelioid and polygonal cells displaying marked nuclear pleomorphism and scattered mitoses (H&E, original magnification ×400).
Figure 4. High-power view of the tumor from the amputation specimen showed sheets of epithelioid and polygonal cells displaying marked nuclear pleomorphism and scattered mitoses (H&amp;E, original magnification ×400).

Cytogenetic studies have failed to identify a consistent chromosomal abnormality in ES.5 Some analyses performed by comparative genomic hybridization on isolated cases and small case series indicate that the most frequent alterations involve 8q, 18q11, and 22q11.13,28,29 The tumor suppressor gene SMARCB1/INI1 (SWI/SNF related, matrix associated, actin dependent regulator of chromatin, subfamily B, member 1/integrase interactor 1) has been mapped to 22q11, and ES commonly shows absence of nuclear staining for this protein, indicating inactivation.13-15

Conclusion

Benign fibrohistiocytic proliferations should be included in the differential of histological mimickers of ES. Deep biopsies are essential to differentiate these benign tumors from fibrous histiocytomalike or fibromalike lesions of ES because superficial portions of ES may be well differentiated.

References

 

1. Enzinger FM. Epitheloid sarcoma. a sarcoma simulating a granuloma or a carcinoma. Cancer. 1970;26:1029-1041.

2. Spillane AJ, Thomas JM, Fisher C. Epithelioid sarcoma: the clinicopathological complexities of this rare soft tissue sarcoma. Ann Surg Oncol. 2000;7:218-225.

3. Chase DR, Enzinger FM. Epithelioid sarcoma. diagnosis, prognostic indicators, and treatment. Am J Surg Pathol. 1985;9:241-263.

4. Fisher C. Epithelioid sarcoma of Enzinger. Adv Anat Pathol. 2006;13:114-121.

5. Evans HL, Baer SC. Epithelioid sarcoma: a clinicopathologic and prognostic study of 26 cases. Semin Diagn Pathol. 1993;10:286-291.

6. Heenan PJ, Quirk CJ, Papadimitriou JM. Epithelioid sarcoma. a diagnostic problem. Am J Dermatopathol. 1986;8:95-104.

7. DiCaudo DJ, McCalmont TH, Wick MR. Selected diagnostic problems in neoplastic dermatopathology. Arch Pathol Lab Med. 2007;131:434-439.

8. Ormsby AH, Liou LS, Oriba HA, et al. Epithelioid sarcoma of the penis: report of an unusual case and review of the literature. Ann Diagn Pathol. 2000;4:88-94.

9. Lowentritt B, Parsons JK, Argani P, et al. Pediatric epithelioid sarcoma of the penis. J Urol. 2004;172:296-297.

10. Mirra JM, Kessler S, Bhuta S, et al. The fibroma-like variant of epithelioid sarcoma. a fibrohistiocytic/myoid cell lesion often confused with benign and malignant spindle cell tumors. Cancer. 1992;69:1382-1395.

11. Tan SH, Ong BH. Spindle cell variant of epithelioid sarcoma: an easily misdiagnosed tumour. Australas J Dermatol. 2001;42:139-141.

12. von Hochstetter AR, Grant JW, Meyer VE, et al. Angiomatoid variant of epithelioid sarcoma. the value of immunohistochemistry in the differential diagnosis. Chir Organi Mov. 1990;75(suppl 1):158-162.

13. Modena P, Lualdi E, Facchinetti F, et al. SMARCB1/INI1 tumor suppressor gene is frequently inactivated in epithelioid sarcomas. Cancer Res. 2005;65:4012-4019.

14. Lualdi E, Modena P, Debiec-Rychter M, et al. Molecular cytogenetic characterization of proximal-type epithelioid sarcoma. Genes Chromosomes Cancer. 2004;41:283-290.

15. Kosemehmetoglu K, Kaygusuz G, Bahrami A, et al. Intra-articular epithelioid sarcoma showing mixed classic and proximal-type features: report of 2 cases, with immunohistochemical and molecular cytogenetic INI-1 study. Am J Surg Pathol. 2011;35:891-897.

16. Armah HB, Parwani AV. Epithelioid sarcoma. Arch Pathol Lab Med. 2009;133:814-819.

17. Fisher C. Epithelioid sarcoma: the spectrum of ultrastructural differentiation in seven immunohistochemically defined cases. Hum Pathol. 1988;19:265-275.

18. Miettinen M, Fanburg-Smith JC, Virolainen M, et al. Epithelioid sarcoma: an immunohistochemical analysis of 112 classical and variant cases and a discussion of the differential diagnosis. Hum Pathol. 1999;30:934-942.

19. Humble SD, Prieto VG, Horenstein MG. Cytokeratin 7 and 20 expression in epithelioid sarcoma. J Cutan Pathol. 2003;30:242-246.

20. Lin L, Skacel M, Sigel JE, et al. Epithelioid sarcoma: an immunohistochemical analysis evaluating the utility of cytokeratin 5/6 in distinguishing superficial epithelioid sarcoma from spindled squamous cell carcinoma. J Cutan Pathol. 2003;30:114-117.

21. Kato H, Hatori M, Kokubun S, et al. CA125 expression in epithelioid sarcoma. Jpn J Clin Oncol. 2004;34:149-154.

22. Kato H, Hatori M, Watanabe M, et al. Epithelioid sarcomas with elevated serum CA125: report of two cases. Jpn J Clin Oncol. 2003;33:141-144.

23. Hoshino M, Kawashima H, Ogose A, et al. Serum CA 125 expression as a tumor marker for the diagnosis and monitoring the clinical course of epithelioid sarcoma [published online ahead of print September 16, 2009]. J Cancer Res Clin Oncol. 2010;136:457-464.

24. Lee AH, Paish EC, Marchio C, et al. The expression of Wilm’s tumour-1 and CA125 in invasive micropapillary carcinoma of the breast. Histopathology. 2007;51:824-828.

25. Homma S, Satoh H, Kagohashi K, et al. Production of CA125 by human lung cancer cell lines. Clin Exp Med. 2004;4:139-141.

26. Streppel MM, Vincent A, Mukherjee R, et al. Mucin 16 (cancer antigen 125) expression in human tissues and cell lines and correlation with clinical outcome in adenocarcinomas of the pancreas, esophagus, stomach, and colon. Hum Pathol. 2012;42:1755-1763.

27. Wei G, Yuping Z, Jun W, et al. CA125 expression in patients with non-Hodgkin’s lymphoma. Leuk Lymphoma. 2006; 47:1322-1326.

28. Feely MG, Fidler ME, Nelson M, et al. Cytogenetic findings in a case of epithelioid sarcoma and a review of the literature. Cancer Genet Cytogenet. 2000;119:155-157.

29. Lushnikova T, Knuutila S, Miettinen M. DNA copy number changes in epithelioid sarcoma and its variants: a comparative genomic hybridization study. Mod Pathol. 2000;13:1092-1096.

Article PDF
CT095020083.pdf
Author and Disclosure Information

 

Michael C. Lynch, MD; Emmy M. Graber, MD, MBA; T. Shane Johnson, MD; Loren E. Clarke, MD

Drs. Lynch and Clarke are from the Department of Pathology and Dr. Johnson is from the Department of Plastic Surgery, all at Penn State Hershey Medical Center, Hershey, Pennsylvania. Dr. Graber is from the Department of Dermatology, Boston University, Massachusetts.

The authors report no conflict of interest.

Correspondence: Michael C. Lynch, MD, Department of Pathology H179, Penn State Hershey Medical Center, 500 University Dr, PO Box 850, Hershey, PA 17033 (mlynch1@hmc.psu.edu).

Issue
Cutis - 95(2)
Publications
Cutis
MDedge Dermatology
Topics
Dermatopathology
Page Number
83-86
Legacy Keywords
epithelioid sarcoma, soft tissue neoplasm, sarcoma, histiocytoma, Staphylococcus aureus, giant cell tumor, fibromatosis, nonhealing lesion, recurrent lesion, benign fibrous histiocytoma
Sections
Case Reports
Author(s)
Michael C. Lynch, MD
Emmy M. Graber, MD, MBA
T. Shane Johnson, MD
Author(s)
Michael C. Lynch, MD
Emmy M. Graber, MD, MBA
T. Shane Johnson, MD
Author and Disclosure Information

 

Michael C. Lynch, MD; Emmy M. Graber, MD, MBA; T. Shane Johnson, MD; Loren E. Clarke, MD

Drs. Lynch and Clarke are from the Department of Pathology and Dr. Johnson is from the Department of Plastic Surgery, all at Penn State Hershey Medical Center, Hershey, Pennsylvania. Dr. Graber is from the Department of Dermatology, Boston University, Massachusetts.

The authors report no conflict of interest.

Correspondence: Michael C. Lynch, MD, Department of Pathology H179, Penn State Hershey Medical Center, 500 University Dr, PO Box 850, Hershey, PA 17033 (mlynch1@hmc.psu.edu).

Author and Disclosure Information

 

Michael C. Lynch, MD; Emmy M. Graber, MD, MBA; T. Shane Johnson, MD; Loren E. Clarke, MD

Drs. Lynch and Clarke are from the Department of Pathology and Dr. Johnson is from the Department of Plastic Surgery, all at Penn State Hershey Medical Center, Hershey, Pennsylvania. Dr. Graber is from the Department of Dermatology, Boston University, Massachusetts.

The authors report no conflict of interest.

Correspondence: Michael C. Lynch, MD, Department of Pathology H179, Penn State Hershey Medical Center, 500 University Dr, PO Box 850, Hershey, PA 17033 (mlynch1@hmc.psu.edu).

Article PDF
CT095020083.pdf
Article PDF
CT095020083.pdf
Related Articles
Cutaneous Malignant Fibrous Histiocytoma With the Characteristics of Different Variants
Verrucous Cobblestonelike Papules and Nodules of the Right Lower Limb

Epithelioid sarcoma (ES) is a rare malignant soft tissue neoplasm that is most often encountered on the distal extremities of young adults.1 Epithelioid sarcoma is notorious for its tendency to mimic palisading granulomatous processes such as granuloma annulare. We report a case of ES on the right hand of a 23-year-old man that resembled a benign fibrous histiocytoma (dermatofibroma) on incisional biopsy. The typical histopathologic features of ES were identified after amputation of the hand and evaluation of the deeper regions of the tumor. The tendency for ES to mimic granulomatous processes is a common diagnostic pitfall, but the potential for its close resemblance to benign fibrous histiocytoma is less recognized.

 

Figure 1. A 0.8×0.6-cm ulcerated nodule on the hypothenar region of the right hand (A). Four months after initial presentation the nodule measured 1.4×1 cm (B).

Case Report

A 23-year-old man presented with a nonhealing lesion on the right palm. His medical history was remarkable for a giant cell tumor of the tendon sheath involving the right fifth finger that had been treated via excision at an outside institution 2 years prior. Clinical examination revealed a 0.8×0.6-cm painful, firm, ulcerated dermal nodule with a hemorrhagic crust on the palmar surface of the right hand (Figure 1A). The clinical differential diagnosis included melanoma, traumatized verruca vulgaris, thrombosed pyogenic granuloma, and foreign body. A shave biopsy demonstrated verrucous epidermal hyperplasia, but the specimen did not include the dermis. Cultures of the lesion were positive for Staphylococcus aureus, and antibiotic therapy was initiated. In light of the clinical findings and the patient’s history of a giant cell tumor, imaging studies were performed. Magnetic resonance angiography showed abnormal masslike infiltrative enhancement throughout the soft tissues surrounding the right fifth metacarpal bone. The differential included a recurrent giant cell tumor, fibromatosis, and other soft tissue neoplasms.

After several missed appointments and surgery cancellations, the patient returned 4 months later for an incisional biopsy. Physical examination revealed a persistent palmar ulcer that had grown to 1.4×1 cm in size, along with an indurated purple plaque wrapping around the ulnar aspect of the right hand (Figure 1B). The biopsy demonstrated a proliferation of spindled and ovoid cells with scant cytoplasm that surrounded sclerotic collagen bundles resembling a dermatofibroma (Figure 2A). Cytologic atypia and mitotic activity were absent (Figure 2B). Glass slides of the original biopsy, which ultimately led to the diagnosis of the giant cell tumor of the tendon sheath more than 2 years earlier, were obtained and showed similar features. The proliferating cells were strongly and diffusely immunoreactive for vimentin, CD34, and cancer antigen 125 (CA 125). Scattered tumor cells strongly expressed cytokeratins (CKs) AE1/AE3 and cell adhesion molecule 5.2 (Figure 3). Staining for CD99 and epithelial membrane antigen was diffuse but weak. Factor XIIIa, S-100, CK7, smooth muscle actin, muscle-specific actin (HHF35), CD31, CD68, and B-cell lymphoma 2 were negative within the proliferating cells. Based on the clinical examination and results of the immunohistochemical staining, a diagnosis of ES was favored.

 

Figure 2. Low-power view of an incisional biopsy resembled a fibrohistiocytomalike neoplasm, as the tumor was composed of plump spindle cells that trapped sclerotic collagen bundles (A)(H&E, original magnification ×40). The tumor lacked significant cytologic atypia and mitotic figures were not seen (B)(H&E, original magnification ×200).

 

After a negative metastatic workup, amputation of the right hand was performed. The amputation specimen showed a tumor that extended through the entire hand with encasement of large vessels and tendons. Although the more superficial regions were cytologically bland, deep-seated regions of the tumor exhibited greater cellularity, nuclear pleomorphism, and mitotic activity (Figure 4). There was no bone involvement. Right axillary sentinel lymph nodes were negative for metastasis. Eighteen months later the patient developed chest and back pain with dyspnea. Thorascopic surgery was performed for a left pleural effusion and metastases to the left parietal pleura and adjacent soft tissue were identified. The patient was subsequently lost to follow-up.

Comment

First described by Enzinger1 in 1970, ES is a rare malignant soft tissue neoplasm that most frequently arises on the hands, forearms, and pretibial soft tissues of young adults.1-3 It is an aggressive tumor characterized by frequent recurrences and a high metastatic rate, with lung and regional lymph nodes being favored metastatic sites.1-5 Periods of several months or even years often pass between the initial presentation and establishment of a correct diagnosis, as ES frequently is mistaken for other benign conditions. The tendency for ES to mimic granulomatous processes is a common diagnostic pitfall, but the potential for its close resemblance to benign fibrous histiocytoma is less recognized.6,7 In his original series of 62 cases, Enzinger1 noted that 17 patients were referred for treatment with a diagnosis of a benign fibrohistiocytic neoplasm, and other reports have described a resemblance to fibrous and fibrohistiocytic neoplasms.8-11 Mirra et al10 designated these tumors as fibromalike variants of ES. Additional subtypes of ES have subsequently been recognized, including those described as angiomatoid or angiosarcomalike, reflecting the potential of ES to resemble vascular tumors.12 A proximal type of ES also has been described. This lesion presents as a deep-seated tumor on the proximal limbs and is associated with more aggressive behavior. It lacks the granulomalike pattern and has more prominent epithelioid and rhabdoid histological presentation.13-15

 

 

Epithelioid sarcoma is a mesenchymal tumor that can display multidirectional differentiation that is primarily epithelial.16 The precise histogenesis of ES remains unclear, but studies have demonstrated a spectrum of differentiation that ranges from primitive myofibroblast or fibrohistiocytelike cells to those with well-developed epithelial properties.16,17 Epithelioid sarcoma characteristically coexpresses vimentin and low-molecular-weight CKs such as cell adhesion molecule 5.2. The tumor cells often are immunoreactive for epithelial membrane antigen and more than 50% of cases exhibit remarkable CD34 positivity.16 More recent studies have further refined the immunophenotype, demonstrating frequent expression of CK8 and CK19 but less commonly CK7, CK20, CK34bE12, and CK5/6.18-20 Additional studies reported that in 10 of 11 cases, ES was positive for CA 125 on immunohistochemical staining, and 3 of 5 patients also had elevated serum CA 125 levels.21,22 More recently, Hoshino et al23 showed elevated serum CA 125 levels in 5 of 7 patients with ES. Cancer antigen 125 is a high-molecular-weight glycoprotein commonly used in the identification of epithelial ovarian carcinomas; however, it also has been described in a number of other neoplasms including carcinomas of the breast, lungs, and colon and lymphoma.24-27 Although it appears that the addition of CA 125 to a panel of other immunohistochemical stains may be helpful in differentiating ES from other soft tissue sarcomas and serum CA 125 levels may help determine tumor burden, currently the number of cases studied is too small to definitively make that conclusion.21,23 In our case, the tumor cells were strongly and diffusely positive for CA 125. Serum CA 125 levels were not available.

 

Figure 3. Tumor cells focally showed strong membranous staining for cytokeratin AE1/AE3 (original magnification ×400).
Figure 3. Tumor cells focally showed strong membranous staining for cytokeratin AE1/AE3 (original magnification ×400).

 

 

Figure 4. High-power view of the tumor from the amputation specimen showed sheets of epithelioid and polygonal cells displaying marked nuclear pleomorphism and scattered mitoses (H&E, original magnification ×400).
Figure 4. High-power view of the tumor from the amputation specimen showed sheets of epithelioid and polygonal cells displaying marked nuclear pleomorphism and scattered mitoses (H&amp;E, original magnification ×400).

Cytogenetic studies have failed to identify a consistent chromosomal abnormality in ES.5 Some analyses performed by comparative genomic hybridization on isolated cases and small case series indicate that the most frequent alterations involve 8q, 18q11, and 22q11.13,28,29 The tumor suppressor gene SMARCB1/INI1 (SWI/SNF related, matrix associated, actin dependent regulator of chromatin, subfamily B, member 1/integrase interactor 1) has been mapped to 22q11, and ES commonly shows absence of nuclear staining for this protein, indicating inactivation.13-15

Conclusion

Benign fibrohistiocytic proliferations should be included in the differential of histological mimickers of ES. Deep biopsies are essential to differentiate these benign tumors from fibrous histiocytomalike or fibromalike lesions of ES because superficial portions of ES may be well differentiated.

Epithelioid sarcoma (ES) is a rare malignant soft tissue neoplasm that is most often encountered on the distal extremities of young adults.1 Epithelioid sarcoma is notorious for its tendency to mimic palisading granulomatous processes such as granuloma annulare. We report a case of ES on the right hand of a 23-year-old man that resembled a benign fibrous histiocytoma (dermatofibroma) on incisional biopsy. The typical histopathologic features of ES were identified after amputation of the hand and evaluation of the deeper regions of the tumor. The tendency for ES to mimic granulomatous processes is a common diagnostic pitfall, but the potential for its close resemblance to benign fibrous histiocytoma is less recognized.

 

Figure 1. A 0.8×0.6-cm ulcerated nodule on the hypothenar region of the right hand (A). Four months after initial presentation the nodule measured 1.4×1 cm (B).

Case Report

A 23-year-old man presented with a nonhealing lesion on the right palm. His medical history was remarkable for a giant cell tumor of the tendon sheath involving the right fifth finger that had been treated via excision at an outside institution 2 years prior. Clinical examination revealed a 0.8×0.6-cm painful, firm, ulcerated dermal nodule with a hemorrhagic crust on the palmar surface of the right hand (Figure 1A). The clinical differential diagnosis included melanoma, traumatized verruca vulgaris, thrombosed pyogenic granuloma, and foreign body. A shave biopsy demonstrated verrucous epidermal hyperplasia, but the specimen did not include the dermis. Cultures of the lesion were positive for Staphylococcus aureus, and antibiotic therapy was initiated. In light of the clinical findings and the patient’s history of a giant cell tumor, imaging studies were performed. Magnetic resonance angiography showed abnormal masslike infiltrative enhancement throughout the soft tissues surrounding the right fifth metacarpal bone. The differential included a recurrent giant cell tumor, fibromatosis, and other soft tissue neoplasms.

After several missed appointments and surgery cancellations, the patient returned 4 months later for an incisional biopsy. Physical examination revealed a persistent palmar ulcer that had grown to 1.4×1 cm in size, along with an indurated purple plaque wrapping around the ulnar aspect of the right hand (Figure 1B). The biopsy demonstrated a proliferation of spindled and ovoid cells with scant cytoplasm that surrounded sclerotic collagen bundles resembling a dermatofibroma (Figure 2A). Cytologic atypia and mitotic activity were absent (Figure 2B). Glass slides of the original biopsy, which ultimately led to the diagnosis of the giant cell tumor of the tendon sheath more than 2 years earlier, were obtained and showed similar features. The proliferating cells were strongly and diffusely immunoreactive for vimentin, CD34, and cancer antigen 125 (CA 125). Scattered tumor cells strongly expressed cytokeratins (CKs) AE1/AE3 and cell adhesion molecule 5.2 (Figure 3). Staining for CD99 and epithelial membrane antigen was diffuse but weak. Factor XIIIa, S-100, CK7, smooth muscle actin, muscle-specific actin (HHF35), CD31, CD68, and B-cell lymphoma 2 were negative within the proliferating cells. Based on the clinical examination and results of the immunohistochemical staining, a diagnosis of ES was favored.

 

Figure 2. Low-power view of an incisional biopsy resembled a fibrohistiocytomalike neoplasm, as the tumor was composed of plump spindle cells that trapped sclerotic collagen bundles (A)(H&E, original magnification ×40). The tumor lacked significant cytologic atypia and mitotic figures were not seen (B)(H&E, original magnification ×200).

 

After a negative metastatic workup, amputation of the right hand was performed. The amputation specimen showed a tumor that extended through the entire hand with encasement of large vessels and tendons. Although the more superficial regions were cytologically bland, deep-seated regions of the tumor exhibited greater cellularity, nuclear pleomorphism, and mitotic activity (Figure 4). There was no bone involvement. Right axillary sentinel lymph nodes were negative for metastasis. Eighteen months later the patient developed chest and back pain with dyspnea. Thorascopic surgery was performed for a left pleural effusion and metastases to the left parietal pleura and adjacent soft tissue were identified. The patient was subsequently lost to follow-up.

Comment

First described by Enzinger1 in 1970, ES is a rare malignant soft tissue neoplasm that most frequently arises on the hands, forearms, and pretibial soft tissues of young adults.1-3 It is an aggressive tumor characterized by frequent recurrences and a high metastatic rate, with lung and regional lymph nodes being favored metastatic sites.1-5 Periods of several months or even years often pass between the initial presentation and establishment of a correct diagnosis, as ES frequently is mistaken for other benign conditions. The tendency for ES to mimic granulomatous processes is a common diagnostic pitfall, but the potential for its close resemblance to benign fibrous histiocytoma is less recognized.6,7 In his original series of 62 cases, Enzinger1 noted that 17 patients were referred for treatment with a diagnosis of a benign fibrohistiocytic neoplasm, and other reports have described a resemblance to fibrous and fibrohistiocytic neoplasms.8-11 Mirra et al10 designated these tumors as fibromalike variants of ES. Additional subtypes of ES have subsequently been recognized, including those described as angiomatoid or angiosarcomalike, reflecting the potential of ES to resemble vascular tumors.12 A proximal type of ES also has been described. This lesion presents as a deep-seated tumor on the proximal limbs and is associated with more aggressive behavior. It lacks the granulomalike pattern and has more prominent epithelioid and rhabdoid histological presentation.13-15

 

 

Epithelioid sarcoma is a mesenchymal tumor that can display multidirectional differentiation that is primarily epithelial.16 The precise histogenesis of ES remains unclear, but studies have demonstrated a spectrum of differentiation that ranges from primitive myofibroblast or fibrohistiocytelike cells to those with well-developed epithelial properties.16,17 Epithelioid sarcoma characteristically coexpresses vimentin and low-molecular-weight CKs such as cell adhesion molecule 5.2. The tumor cells often are immunoreactive for epithelial membrane antigen and more than 50% of cases exhibit remarkable CD34 positivity.16 More recent studies have further refined the immunophenotype, demonstrating frequent expression of CK8 and CK19 but less commonly CK7, CK20, CK34bE12, and CK5/6.18-20 Additional studies reported that in 10 of 11 cases, ES was positive for CA 125 on immunohistochemical staining, and 3 of 5 patients also had elevated serum CA 125 levels.21,22 More recently, Hoshino et al23 showed elevated serum CA 125 levels in 5 of 7 patients with ES. Cancer antigen 125 is a high-molecular-weight glycoprotein commonly used in the identification of epithelial ovarian carcinomas; however, it also has been described in a number of other neoplasms including carcinomas of the breast, lungs, and colon and lymphoma.24-27 Although it appears that the addition of CA 125 to a panel of other immunohistochemical stains may be helpful in differentiating ES from other soft tissue sarcomas and serum CA 125 levels may help determine tumor burden, currently the number of cases studied is too small to definitively make that conclusion.21,23 In our case, the tumor cells were strongly and diffusely positive for CA 125. Serum CA 125 levels were not available.

 

Figure 3. Tumor cells focally showed strong membranous staining for cytokeratin AE1/AE3 (original magnification ×400).
Figure 3. Tumor cells focally showed strong membranous staining for cytokeratin AE1/AE3 (original magnification ×400).

 

 

Figure 4. High-power view of the tumor from the amputation specimen showed sheets of epithelioid and polygonal cells displaying marked nuclear pleomorphism and scattered mitoses (H&E, original magnification ×400).
Figure 4. High-power view of the tumor from the amputation specimen showed sheets of epithelioid and polygonal cells displaying marked nuclear pleomorphism and scattered mitoses (H&amp;E, original magnification ×400).

Cytogenetic studies have failed to identify a consistent chromosomal abnormality in ES.5 Some analyses performed by comparative genomic hybridization on isolated cases and small case series indicate that the most frequent alterations involve 8q, 18q11, and 22q11.13,28,29 The tumor suppressor gene SMARCB1/INI1 (SWI/SNF related, matrix associated, actin dependent regulator of chromatin, subfamily B, member 1/integrase interactor 1) has been mapped to 22q11, and ES commonly shows absence of nuclear staining for this protein, indicating inactivation.13-15

Conclusion

Benign fibrohistiocytic proliferations should be included in the differential of histological mimickers of ES. Deep biopsies are essential to differentiate these benign tumors from fibrous histiocytomalike or fibromalike lesions of ES because superficial portions of ES may be well differentiated.

References

 

1. Enzinger FM. Epitheloid sarcoma. a sarcoma simulating a granuloma or a carcinoma. Cancer. 1970;26:1029-1041.

2. Spillane AJ, Thomas JM, Fisher C. Epithelioid sarcoma: the clinicopathological complexities of this rare soft tissue sarcoma. Ann Surg Oncol. 2000;7:218-225.

3. Chase DR, Enzinger FM. Epithelioid sarcoma. diagnosis, prognostic indicators, and treatment. Am J Surg Pathol. 1985;9:241-263.

4. Fisher C. Epithelioid sarcoma of Enzinger. Adv Anat Pathol. 2006;13:114-121.

5. Evans HL, Baer SC. Epithelioid sarcoma: a clinicopathologic and prognostic study of 26 cases. Semin Diagn Pathol. 1993;10:286-291.

6. Heenan PJ, Quirk CJ, Papadimitriou JM. Epithelioid sarcoma. a diagnostic problem. Am J Dermatopathol. 1986;8:95-104.

7. DiCaudo DJ, McCalmont TH, Wick MR. Selected diagnostic problems in neoplastic dermatopathology. Arch Pathol Lab Med. 2007;131:434-439.

8. Ormsby AH, Liou LS, Oriba HA, et al. Epithelioid sarcoma of the penis: report of an unusual case and review of the literature. Ann Diagn Pathol. 2000;4:88-94.

9. Lowentritt B, Parsons JK, Argani P, et al. Pediatric epithelioid sarcoma of the penis. J Urol. 2004;172:296-297.

10. Mirra JM, Kessler S, Bhuta S, et al. The fibroma-like variant of epithelioid sarcoma. a fibrohistiocytic/myoid cell lesion often confused with benign and malignant spindle cell tumors. Cancer. 1992;69:1382-1395.

11. Tan SH, Ong BH. Spindle cell variant of epithelioid sarcoma: an easily misdiagnosed tumour. Australas J Dermatol. 2001;42:139-141.

12. von Hochstetter AR, Grant JW, Meyer VE, et al. Angiomatoid variant of epithelioid sarcoma. the value of immunohistochemistry in the differential diagnosis. Chir Organi Mov. 1990;75(suppl 1):158-162.

13. Modena P, Lualdi E, Facchinetti F, et al. SMARCB1/INI1 tumor suppressor gene is frequently inactivated in epithelioid sarcomas. Cancer Res. 2005;65:4012-4019.

14. Lualdi E, Modena P, Debiec-Rychter M, et al. Molecular cytogenetic characterization of proximal-type epithelioid sarcoma. Genes Chromosomes Cancer. 2004;41:283-290.

15. Kosemehmetoglu K, Kaygusuz G, Bahrami A, et al. Intra-articular epithelioid sarcoma showing mixed classic and proximal-type features: report of 2 cases, with immunohistochemical and molecular cytogenetic INI-1 study. Am J Surg Pathol. 2011;35:891-897.

16. Armah HB, Parwani AV. Epithelioid sarcoma. Arch Pathol Lab Med. 2009;133:814-819.

17. Fisher C. Epithelioid sarcoma: the spectrum of ultrastructural differentiation in seven immunohistochemically defined cases. Hum Pathol. 1988;19:265-275.

18. Miettinen M, Fanburg-Smith JC, Virolainen M, et al. Epithelioid sarcoma: an immunohistochemical analysis of 112 classical and variant cases and a discussion of the differential diagnosis. Hum Pathol. 1999;30:934-942.

19. Humble SD, Prieto VG, Horenstein MG. Cytokeratin 7 and 20 expression in epithelioid sarcoma. J Cutan Pathol. 2003;30:242-246.

20. Lin L, Skacel M, Sigel JE, et al. Epithelioid sarcoma: an immunohistochemical analysis evaluating the utility of cytokeratin 5/6 in distinguishing superficial epithelioid sarcoma from spindled squamous cell carcinoma. J Cutan Pathol. 2003;30:114-117.

21. Kato H, Hatori M, Kokubun S, et al. CA125 expression in epithelioid sarcoma. Jpn J Clin Oncol. 2004;34:149-154.

22. Kato H, Hatori M, Watanabe M, et al. Epithelioid sarcomas with elevated serum CA125: report of two cases. Jpn J Clin Oncol. 2003;33:141-144.

23. Hoshino M, Kawashima H, Ogose A, et al. Serum CA 125 expression as a tumor marker for the diagnosis and monitoring the clinical course of epithelioid sarcoma [published online ahead of print September 16, 2009]. J Cancer Res Clin Oncol. 2010;136:457-464.

24. Lee AH, Paish EC, Marchio C, et al. The expression of Wilm’s tumour-1 and CA125 in invasive micropapillary carcinoma of the breast. Histopathology. 2007;51:824-828.

25. Homma S, Satoh H, Kagohashi K, et al. Production of CA125 by human lung cancer cell lines. Clin Exp Med. 2004;4:139-141.

26. Streppel MM, Vincent A, Mukherjee R, et al. Mucin 16 (cancer antigen 125) expression in human tissues and cell lines and correlation with clinical outcome in adenocarcinomas of the pancreas, esophagus, stomach, and colon. Hum Pathol. 2012;42:1755-1763.

27. Wei G, Yuping Z, Jun W, et al. CA125 expression in patients with non-Hodgkin’s lymphoma. Leuk Lymphoma. 2006; 47:1322-1326.

28. Feely MG, Fidler ME, Nelson M, et al. Cytogenetic findings in a case of epithelioid sarcoma and a review of the literature. Cancer Genet Cytogenet. 2000;119:155-157.

29. Lushnikova T, Knuutila S, Miettinen M. DNA copy number changes in epithelioid sarcoma and its variants: a comparative genomic hybridization study. Mod Pathol. 2000;13:1092-1096.

References

 

1. Enzinger FM. Epitheloid sarcoma. a sarcoma simulating a granuloma or a carcinoma. Cancer. 1970;26:1029-1041.

2. Spillane AJ, Thomas JM, Fisher C. Epithelioid sarcoma: the clinicopathological complexities of this rare soft tissue sarcoma. Ann Surg Oncol. 2000;7:218-225.

3. Chase DR, Enzinger FM. Epithelioid sarcoma. diagnosis, prognostic indicators, and treatment. Am J Surg Pathol. 1985;9:241-263.

4. Fisher C. Epithelioid sarcoma of Enzinger. Adv Anat Pathol. 2006;13:114-121.

5. Evans HL, Baer SC. Epithelioid sarcoma: a clinicopathologic and prognostic study of 26 cases. Semin Diagn Pathol. 1993;10:286-291.

6. Heenan PJ, Quirk CJ, Papadimitriou JM. Epithelioid sarcoma. a diagnostic problem. Am J Dermatopathol. 1986;8:95-104.

7. DiCaudo DJ, McCalmont TH, Wick MR. Selected diagnostic problems in neoplastic dermatopathology. Arch Pathol Lab Med. 2007;131:434-439.

8. Ormsby AH, Liou LS, Oriba HA, et al. Epithelioid sarcoma of the penis: report of an unusual case and review of the literature. Ann Diagn Pathol. 2000;4:88-94.

9. Lowentritt B, Parsons JK, Argani P, et al. Pediatric epithelioid sarcoma of the penis. J Urol. 2004;172:296-297.

10. Mirra JM, Kessler S, Bhuta S, et al. The fibroma-like variant of epithelioid sarcoma. a fibrohistiocytic/myoid cell lesion often confused with benign and malignant spindle cell tumors. Cancer. 1992;69:1382-1395.

11. Tan SH, Ong BH. Spindle cell variant of epithelioid sarcoma: an easily misdiagnosed tumour. Australas J Dermatol. 2001;42:139-141.

12. von Hochstetter AR, Grant JW, Meyer VE, et al. Angiomatoid variant of epithelioid sarcoma. the value of immunohistochemistry in the differential diagnosis. Chir Organi Mov. 1990;75(suppl 1):158-162.

13. Modena P, Lualdi E, Facchinetti F, et al. SMARCB1/INI1 tumor suppressor gene is frequently inactivated in epithelioid sarcomas. Cancer Res. 2005;65:4012-4019.

14. Lualdi E, Modena P, Debiec-Rychter M, et al. Molecular cytogenetic characterization of proximal-type epithelioid sarcoma. Genes Chromosomes Cancer. 2004;41:283-290.

15. Kosemehmetoglu K, Kaygusuz G, Bahrami A, et al. Intra-articular epithelioid sarcoma showing mixed classic and proximal-type features: report of 2 cases, with immunohistochemical and molecular cytogenetic INI-1 study. Am J Surg Pathol. 2011;35:891-897.

16. Armah HB, Parwani AV. Epithelioid sarcoma. Arch Pathol Lab Med. 2009;133:814-819.

17. Fisher C. Epithelioid sarcoma: the spectrum of ultrastructural differentiation in seven immunohistochemically defined cases. Hum Pathol. 1988;19:265-275.

18. Miettinen M, Fanburg-Smith JC, Virolainen M, et al. Epithelioid sarcoma: an immunohistochemical analysis of 112 classical and variant cases and a discussion of the differential diagnosis. Hum Pathol. 1999;30:934-942.

19. Humble SD, Prieto VG, Horenstein MG. Cytokeratin 7 and 20 expression in epithelioid sarcoma. J Cutan Pathol. 2003;30:242-246.

20. Lin L, Skacel M, Sigel JE, et al. Epithelioid sarcoma: an immunohistochemical analysis evaluating the utility of cytokeratin 5/6 in distinguishing superficial epithelioid sarcoma from spindled squamous cell carcinoma. J Cutan Pathol. 2003;30:114-117.

21. Kato H, Hatori M, Kokubun S, et al. CA125 expression in epithelioid sarcoma. Jpn J Clin Oncol. 2004;34:149-154.

22. Kato H, Hatori M, Watanabe M, et al. Epithelioid sarcomas with elevated serum CA125: report of two cases. Jpn J Clin Oncol. 2003;33:141-144.

23. Hoshino M, Kawashima H, Ogose A, et al. Serum CA 125 expression as a tumor marker for the diagnosis and monitoring the clinical course of epithelioid sarcoma [published online ahead of print September 16, 2009]. J Cancer Res Clin Oncol. 2010;136:457-464.

24. Lee AH, Paish EC, Marchio C, et al. The expression of Wilm’s tumour-1 and CA125 in invasive micropapillary carcinoma of the breast. Histopathology. 2007;51:824-828.

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Issue
Cutis - 95(2)
Issue
Cutis - 95(2)
Page Number
83-86
Page Number
83-86
Publications
Cutis
MDedge Dermatology
Publications
Cutis
MDedge Dermatology
Topics
Dermatopathology
Article Type
Article
Display Headline
Epithelioid Sarcoma Resembling Benign Fibrous Histiocytoma
Display Headline
Epithelioid Sarcoma Resembling Benign Fibrous Histiocytoma
Legacy Keywords
epithelioid sarcoma, soft tissue neoplasm, sarcoma, histiocytoma, Staphylococcus aureus, giant cell tumor, fibromatosis, nonhealing lesion, recurrent lesion, benign fibrous histiocytoma
Legacy Keywords
epithelioid sarcoma, soft tissue neoplasm, sarcoma, histiocytoma, Staphylococcus aureus, giant cell tumor, fibromatosis, nonhealing lesion, recurrent lesion, benign fibrous histiocytoma
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Case Reports
Inside the Article

       Practice Points

 

  • ­Epithelioid sarcoma should be considered in the clinical differential diagnosis of nonhealing recurrent lesions of the distal extremities in a young adult.
  • ­Histological presentation of epithelioid sarcoma can mimic a number of benign granulomatous and fibrohistiocytic processes, including benign fibrous histiocytoma.
  • ­Deeper biopsies may be needed to demonstrate the overtly malignant morphology characteristic of epithelioid sarcoma.
  • ­Inactivation of SMARCB1/INI1 is a common molecular aberration identified in epithelioid sarcoma and can be demonstrated immunohistochemically by absence of nuclear staining in tumor cells.
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