Stanislav N. Tolkachjov, MD

Minoxidil, a potent vasodilator, was approved by the US Food and Drug Administration (FDA) in 1963 to treat high blood pressure. Its application as a hair loss treatment was discovered by accident—patients taking oral minoxidil for blood pressure noticed hair growth on their bodies as a side effect of the medication. In 1988, topical minoxidil (Rogaine [Johnson & Johnson Consumer Inc]) was approved by the FDA for the treatment of androgenetic alopecia in men, and then it was approved for the same indication in women in 1991. The mechanism of action by which minoxidil increases hair growth still has not been fully elucidated. When applied topically, it is thought to extend the anagen phase (or growth phase) of the hair cycle and increase hair follicle size. It also increases oxygen to the hair follicle through vasodilation and stimulates the production of vascular endothelial growth factor, which is thought to promote hair growth.¹ Since its approval, topical minoxidil has become a first-line treatment of androgenetic alopecia in men and women.

In August 2022, The New York Times (NYT) published an article on dermatologists’ use of oral minoxidil at a fraction of the dose prescribed for blood pressure with profound results in hair regrowth.² Several dermatologists quoted in the article endorsed that the decreased dose minimizes unwanted side effects such as hypertrichosis, hypotension, and other cardiac issues while still being effective for hair loss. Also, compared to topical minoxidil, low-dose oral minoxidil (LDOM) is relatively cheaper and easier to use; topicals are more cumbersome to apply and often leave the hair and scalp sticky, leading to noncompliance among patients.² Currently, oral minoxidil is not approved by the FDA for use in hair loss, making it an off-label use.

Since the NYT article was published, we have observed an increase in patient questions and requests for LDOM as well as heightened use by fellow dermatologists in our community. As of November 2022, the NYT had approximately 9,330,000 total subscribers, solidifying its place as a newspaper of record in the United States and across the world.³ In April 2023, we conducted a survey of US-based board-certified dermatologists to investigate the impact of the NYT article on prescribing practices of LDOM for alopecia. The survey was conducted as a poll in a Facebook group for board-certified dermatologists and asked, “How did the NYT article on oral minoxidil for alopecia change your utilization of LDOM (low-dose oral minoxidil) for alopecia?” Three answer choices were given: (1) I started Rx’ing LDOM or increased the number of patients I manage with LDOM; (2) No change. I never Rx’d LDOM and/or no increase in utilization; and (3) I was already prescribing LDOM.

Of the 65 total respondents, 27 (42%) reported that the NYT article influenced their decision to start prescribing LDOM for alopecia. Nine respondents (14%) reported that the article did not influence their prescribing habits, and 27 (42%) responded that they were already prescribing the medication prior to the article’s publication.

Data from Epiphany Dermatology, a practice with more than 70 locations throughout the United States, showed that oral minoxidil was prescribed for alopecia 107 times in 2020 and 672 times in 2021 (Amy Hadley, Epiphany Dermatology, written communication, March 24, 2023). In 2022, prescriptions increased exponentially to 1626, and in the period of January 2023 to March 2023 alone, oral minoxidil was prescribed 510 times. Following publication of the NYT article in August 2022, LDOM was prescribed a total of 1377 times in the next 8 months.

Moreover, data from Summit Pharmacy, a retail pharmacy in Centennial, Colorado, showed an 1800% increase in LDOM prescriptions in the 7 months following the NYT article’s publication (August 2022 to March 2023) compared with the 7 months prior (January 2022 to August 2022)(Brandon Johnson, Summit Pharmacy, written communication, March 30, 2023). These data provide evidence for the influence of the NYT article on prescribing habits of dermatology providers in the United States.

The safety of oral minoxidil for use in hair loss has been established through several studies in the literature.^4,5 These results show that LDOM may be a safe, readily accessible, and revolutionary treatment for hair loss. A retrospective multicenter study of 1404 patients treated with LDOM for any type of alopecia found that side effects were infrequent, and only 1.7% of patients discontinued treatment due to adverse effects. The most frequent adverse effect was hypertrichosis, occurring in 15.1% of patients but leading to treatment withdrawal in only 0.5% of patients.⁴ Similarly, Randolph and Tosti⁵ found that hypertrichosis of the face and body was the most common adverse effect observed, though it rarely resulted in discontinuation and likely was dose dependent: less than 10% of patients receiving 0.25 mg/d experienced hypertrichosis compared with more than 50% of those receiving 5 mg/d (N=634). They also described patients in whom topical minoxidil, though effective, posed major barriers to compliance due to the twice-daily application, changes to hair texture from the medication, and scalp irritation. A literature review of 17 studies with 634 patients on LDOM as a primary treatment for hair loss found that it was an effective, well-tolerated treatment and should be considered for healthy patients who have difficulty with topical formulations.⁵

In the age of media with data constantly at users’ fingertips, the art of practicing medicine also has changed. Although physicians pride themselves on evidence-based medicine, it appears that an NYT article had an impact on how physicians, particularly dermatologists, prescribe oral minoxidil. However, it is difficult to know if the article exposed dermatologists to another treatment in their armamentarium for hair loss or if it influenced patients to ask their health care provider about LDOM for hair loss. One thing is clear—since the article’s publication, the off-label use of LDOM for alopecia has produced what many may call “miracles” for patients with hair loss.⁵

Minoxidil, a potent vasodilator, was approved by the US Food and Drug Administration (FDA) in 1963 to treat high blood pressure. Its application as a hair loss treatment was discovered by accident—patients taking oral minoxidil for blood pressure noticed hair growth on their bodies as a side effect of the medication. In 1988, topical minoxidil (Rogaine [Johnson & Johnson Consumer Inc]) was approved by the FDA for the treatment of androgenetic alopecia in men, and then it was approved for the same indication in women in 1991. The mechanism of action by which minoxidil increases hair growth still has not been fully elucidated. When applied topically, it is thought to extend the anagen phase (or growth phase) of the hair cycle and increase hair follicle size. It also increases oxygen to the hair follicle through vasodilation and stimulates the production of vascular endothelial growth factor, which is thought to promote hair growth.¹ Since its approval, topical minoxidil has become a first-line treatment of androgenetic alopecia in men and women.

In August 2022, The New York Times (NYT) published an article on dermatologists’ use of oral minoxidil at a fraction of the dose prescribed for blood pressure with profound results in hair regrowth.² Several dermatologists quoted in the article endorsed that the decreased dose minimizes unwanted side effects such as hypertrichosis, hypotension, and other cardiac issues while still being effective for hair loss. Also, compared to topical minoxidil, low-dose oral minoxidil (LDOM) is relatively cheaper and easier to use; topicals are more cumbersome to apply and often leave the hair and scalp sticky, leading to noncompliance among patients.² Currently, oral minoxidil is not approved by the FDA for use in hair loss, making it an off-label use.

Since the NYT article was published, we have observed an increase in patient questions and requests for LDOM as well as heightened use by fellow dermatologists in our community. As of November 2022, the NYT had approximately 9,330,000 total subscribers, solidifying its place as a newspaper of record in the United States and across the world.³ In April 2023, we conducted a survey of US-based board-certified dermatologists to investigate the impact of the NYT article on prescribing practices of LDOM for alopecia. The survey was conducted as a poll in a Facebook group for board-certified dermatologists and asked, “How did the NYT article on oral minoxidil for alopecia change your utilization of LDOM (low-dose oral minoxidil) for alopecia?” Three answer choices were given: (1) I started Rx’ing LDOM or increased the number of patients I manage with LDOM; (2) No change. I never Rx’d LDOM and/or no increase in utilization; and (3) I was already prescribing LDOM.

Of the 65 total respondents, 27 (42%) reported that the NYT article influenced their decision to start prescribing LDOM for alopecia. Nine respondents (14%) reported that the article did not influence their prescribing habits, and 27 (42%) responded that they were already prescribing the medication prior to the article’s publication.

Data from Epiphany Dermatology, a practice with more than 70 locations throughout the United States, showed that oral minoxidil was prescribed for alopecia 107 times in 2020 and 672 times in 2021 (Amy Hadley, Epiphany Dermatology, written communication, March 24, 2023). In 2022, prescriptions increased exponentially to 1626, and in the period of January 2023 to March 2023 alone, oral minoxidil was prescribed 510 times. Following publication of the NYT article in August 2022, LDOM was prescribed a total of 1377 times in the next 8 months.

Moreover, data from Summit Pharmacy, a retail pharmacy in Centennial, Colorado, showed an 1800% increase in LDOM prescriptions in the 7 months following the NYT article’s publication (August 2022 to March 2023) compared with the 7 months prior (January 2022 to August 2022)(Brandon Johnson, Summit Pharmacy, written communication, March 30, 2023). These data provide evidence for the influence of the NYT article on prescribing habits of dermatology providers in the United States.

The safety of oral minoxidil for use in hair loss has been established through several studies in the literature.^4,5 These results show that LDOM may be a safe, readily accessible, and revolutionary treatment for hair loss. A retrospective multicenter study of 1404 patients treated with LDOM for any type of alopecia found that side effects were infrequent, and only 1.7% of patients discontinued treatment due to adverse effects. The most frequent adverse effect was hypertrichosis, occurring in 15.1% of patients but leading to treatment withdrawal in only 0.5% of patients.⁴ Similarly, Randolph and Tosti⁵ found that hypertrichosis of the face and body was the most common adverse effect observed, though it rarely resulted in discontinuation and likely was dose dependent: less than 10% of patients receiving 0.25 mg/d experienced hypertrichosis compared with more than 50% of those receiving 5 mg/d (N=634). They also described patients in whom topical minoxidil, though effective, posed major barriers to compliance due to the twice-daily application, changes to hair texture from the medication, and scalp irritation. A literature review of 17 studies with 634 patients on LDOM as a primary treatment for hair loss found that it was an effective, well-tolerated treatment and should be considered for healthy patients who have difficulty with topical formulations.⁵

In the age of media with data constantly at users’ fingertips, the art of practicing medicine also has changed. Although physicians pride themselves on evidence-based medicine, it appears that an NYT article had an impact on how physicians, particularly dermatologists, prescribe oral minoxidil. However, it is difficult to know if the article exposed dermatologists to another treatment in their armamentarium for hair loss or if it influenced patients to ask their health care provider about LDOM for hair loss. One thing is clear—since the article’s publication, the off-label use of LDOM for alopecia has produced what many may call “miracles” for patients with hair loss.⁵

Minoxidil, a potent vasodilator, was approved by the US Food and Drug Administration (FDA) in 1963 to treat high blood pressure. Its application as a hair loss treatment was discovered by accident—patients taking oral minoxidil for blood pressure noticed hair growth on their bodies as a side effect of the medication. In 1988, topical minoxidil (Rogaine [Johnson & Johnson Consumer Inc]) was approved by the FDA for the treatment of androgenetic alopecia in men, and then it was approved for the same indication in women in 1991. The mechanism of action by which minoxidil increases hair growth still has not been fully elucidated. When applied topically, it is thought to extend the anagen phase (or growth phase) of the hair cycle and increase hair follicle size. It also increases oxygen to the hair follicle through vasodilation and stimulates the production of vascular endothelial growth factor, which is thought to promote hair growth.¹ Since its approval, topical minoxidil has become a first-line treatment of androgenetic alopecia in men and women.

In August 2022, The New York Times (NYT) published an article on dermatologists’ use of oral minoxidil at a fraction of the dose prescribed for blood pressure with profound results in hair regrowth.² Several dermatologists quoted in the article endorsed that the decreased dose minimizes unwanted side effects such as hypertrichosis, hypotension, and other cardiac issues while still being effective for hair loss. Also, compared to topical minoxidil, low-dose oral minoxidil (LDOM) is relatively cheaper and easier to use; topicals are more cumbersome to apply and often leave the hair and scalp sticky, leading to noncompliance among patients.² Currently, oral minoxidil is not approved by the FDA for use in hair loss, making it an off-label use.

Since the NYT article was published, we have observed an increase in patient questions and requests for LDOM as well as heightened use by fellow dermatologists in our community. As of November 2022, the NYT had approximately 9,330,000 total subscribers, solidifying its place as a newspaper of record in the United States and across the world.³ In April 2023, we conducted a survey of US-based board-certified dermatologists to investigate the impact of the NYT article on prescribing practices of LDOM for alopecia. The survey was conducted as a poll in a Facebook group for board-certified dermatologists and asked, “How did the NYT article on oral minoxidil for alopecia change your utilization of LDOM (low-dose oral minoxidil) for alopecia?” Three answer choices were given: (1) I started Rx’ing LDOM or increased the number of patients I manage with LDOM; (2) No change. I never Rx’d LDOM and/or no increase in utilization; and (3) I was already prescribing LDOM.

Of the 65 total respondents, 27 (42%) reported that the NYT article influenced their decision to start prescribing LDOM for alopecia. Nine respondents (14%) reported that the article did not influence their prescribing habits, and 27 (42%) responded that they were already prescribing the medication prior to the article’s publication.

Data from Epiphany Dermatology, a practice with more than 70 locations throughout the United States, showed that oral minoxidil was prescribed for alopecia 107 times in 2020 and 672 times in 2021 (Amy Hadley, Epiphany Dermatology, written communication, March 24, 2023). In 2022, prescriptions increased exponentially to 1626, and in the period of January 2023 to March 2023 alone, oral minoxidil was prescribed 510 times. Following publication of the NYT article in August 2022, LDOM was prescribed a total of 1377 times in the next 8 months.

Moreover, data from Summit Pharmacy, a retail pharmacy in Centennial, Colorado, showed an 1800% increase in LDOM prescriptions in the 7 months following the NYT article’s publication (August 2022 to March 2023) compared with the 7 months prior (January 2022 to August 2022)(Brandon Johnson, Summit Pharmacy, written communication, March 30, 2023). These data provide evidence for the influence of the NYT article on prescribing habits of dermatology providers in the United States.

The safety of oral minoxidil for use in hair loss has been established through several studies in the literature.^4,5 These results show that LDOM may be a safe, readily accessible, and revolutionary treatment for hair loss. A retrospective multicenter study of 1404 patients treated with LDOM for any type of alopecia found that side effects were infrequent, and only 1.7% of patients discontinued treatment due to adverse effects. The most frequent adverse effect was hypertrichosis, occurring in 15.1% of patients but leading to treatment withdrawal in only 0.5% of patients.⁴ Similarly, Randolph and Tosti⁵ found that hypertrichosis of the face and body was the most common adverse effect observed, though it rarely resulted in discontinuation and likely was dose dependent: less than 10% of patients receiving 0.25 mg/d experienced hypertrichosis compared with more than 50% of those receiving 5 mg/d (N=634). They also described patients in whom topical minoxidil, though effective, posed major barriers to compliance due to the twice-daily application, changes to hair texture from the medication, and scalp irritation. A literature review of 17 studies with 634 patients on LDOM as a primary treatment for hair loss found that it was an effective, well-tolerated treatment and should be considered for healthy patients who have difficulty with topical formulations.⁵

In the age of media with data constantly at users’ fingertips, the art of practicing medicine also has changed. Although physicians pride themselves on evidence-based medicine, it appears that an NYT article had an impact on how physicians, particularly dermatologists, prescribe oral minoxidil. However, it is difficult to know if the article exposed dermatologists to another treatment in their armamentarium for hair loss or if it influenced patients to ask their health care provider about LDOM for hair loss. One thing is clear—since the article’s publication, the off-label use of LDOM for alopecia has produced what many may call “miracles” for patients with hair loss.⁵

Practice Gap

Scalp defects that extend to or below the periosteum often pose a reconstructive conundrum. Secondary-intention healing is challenging without an intact periosteum, and complex rotational flaps are required in these scenarios.¹ For a tumor that is at high risk for recurrence or when adjuvant therapy is necessary, tissue distortion of flaps can make monitoring for recurrence difficult. Similarly, for patients in poor health or who are elderly and have substantial skin atrophy, extensive closure may be undesirable or more technically challenging with a higher risk for adverse events. In these scenarios, additional strategies are necessary to optimize wound healing and cosmesis. A cadaveric split-thickness skin graft (STSG) consisting of biologically active tissue can be used to expedite granulation.²

Technique

Following tumor clearance on the scalp (Figure 1), wide undermining is performed and 3-0 polyglactin 910 epidermal pulley sutures are placed to partially close the defect. A cadaveric STSG is placed over the remaining exposed periosteum and secured under the pulley sutures (Figure 2). The cadaveric STSG is replaced at 1-week intervals. At 4 weeks, sutures typically are removed. The cadaveric STSG is used until the exposed periosteum is fully granulated and the surgeon decides that granulation arrest is unlikely. The wound then heals by unassisted granulation. This approach provides an excellent final cosmetic outcome while avoiding extensive reconstruction (Figure 3).

Practice Implications

Scalp defects requiring closure are common for dermatologic surgeons. Several techniques to promote tissue granulation in defects that involve exposed periosteum have been reported, including (1) creation of small holes with a scalpel or chisel to access cortical circulation and (2) using laser modalities to stimulate granulation (eg, an erbium:YAG or CO₂ laser).^3,4 Although direct comparative studies are needed, the cadaveric STSG provides an approach that increases tissue granulation but does not require more invasive techniques or equipment.

Autologous STSGs need a wound bed and can fail with an exposed periosteum. Furthermore, an autologous STSG that survives may leave an unsightly, hypopigmented, depressed defect. When a defect involves the periosteum and a primary closure or flap is not ideal, a skin substitute may be an option.

Skin substitutes, including cadaveric STSG, generally are classified as bioengineered skin equivalents, amniotic tissue, or cadaveric bioproducts (Table). Unlike autologous grafts, these skin substitutes can provide rapid coverage of the defect and do not require a highly vascularized wound bed.⁶ They also minimize the inflammatory response and potentially improve the final cosmetic outcome by improving granulation rather than immediate STSG closure creating a step-off in deep wounds.⁶

Cadaveric STSGs also have been used in nonhealing ulcerations; diabetic foot ulcers; and ulcerations in which muscle, tendon, or bone are exposed, demonstrating induction of wound healing with superior scar quality and skin function.^2,7,8 The utility of the cadaveric STSG is further highlighted by its potential to reduce costs⁹ compared to bioengineered skin substitutes, though considerable variability exists in pricing (Table).

Consider using a cadaveric STSG with a guiding closure in cases in which there is concern for delayed or absent tissue granulation or when monitoring for recurrence is essential.

Practice Gap

Scalp defects that extend to or below the periosteum often pose a reconstructive conundrum. Secondary-intention healing is challenging without an intact periosteum, and complex rotational flaps are required in these scenarios.¹ For a tumor that is at high risk for recurrence or when adjuvant therapy is necessary, tissue distortion of flaps can make monitoring for recurrence difficult. Similarly, for patients in poor health or who are elderly and have substantial skin atrophy, extensive closure may be undesirable or more technically challenging with a higher risk for adverse events. In these scenarios, additional strategies are necessary to optimize wound healing and cosmesis. A cadaveric split-thickness skin graft (STSG) consisting of biologically active tissue can be used to expedite granulation.²

Technique

Following tumor clearance on the scalp (Figure 1), wide undermining is performed and 3-0 polyglactin 910 epidermal pulley sutures are placed to partially close the defect. A cadaveric STSG is placed over the remaining exposed periosteum and secured under the pulley sutures (Figure 2). The cadaveric STSG is replaced at 1-week intervals. At 4 weeks, sutures typically are removed. The cadaveric STSG is used until the exposed periosteum is fully granulated and the surgeon decides that granulation arrest is unlikely. The wound then heals by unassisted granulation. This approach provides an excellent final cosmetic outcome while avoiding extensive reconstruction (Figure 3).

Practice Implications

Scalp defects requiring closure are common for dermatologic surgeons. Several techniques to promote tissue granulation in defects that involve exposed periosteum have been reported, including (1) creation of small holes with a scalpel or chisel to access cortical circulation and (2) using laser modalities to stimulate granulation (eg, an erbium:YAG or CO₂ laser).^3,4 Although direct comparative studies are needed, the cadaveric STSG provides an approach that increases tissue granulation but does not require more invasive techniques or equipment.

Autologous STSGs need a wound bed and can fail with an exposed periosteum. Furthermore, an autologous STSG that survives may leave an unsightly, hypopigmented, depressed defect. When a defect involves the periosteum and a primary closure or flap is not ideal, a skin substitute may be an option.

Skin substitutes, including cadaveric STSG, generally are classified as bioengineered skin equivalents, amniotic tissue, or cadaveric bioproducts (Table). Unlike autologous grafts, these skin substitutes can provide rapid coverage of the defect and do not require a highly vascularized wound bed.⁶ They also minimize the inflammatory response and potentially improve the final cosmetic outcome by improving granulation rather than immediate STSG closure creating a step-off in deep wounds.⁶

Cadaveric STSGs also have been used in nonhealing ulcerations; diabetic foot ulcers; and ulcerations in which muscle, tendon, or bone are exposed, demonstrating induction of wound healing with superior scar quality and skin function.^2,7,8 The utility of the cadaveric STSG is further highlighted by its potential to reduce costs⁹ compared to bioengineered skin substitutes, though considerable variability exists in pricing (Table).

Consider using a cadaveric STSG with a guiding closure in cases in which there is concern for delayed or absent tissue granulation or when monitoring for recurrence is essential.

Practice Gap

Scalp defects that extend to or below the periosteum often pose a reconstructive conundrum. Secondary-intention healing is challenging without an intact periosteum, and complex rotational flaps are required in these scenarios.¹ For a tumor that is at high risk for recurrence or when adjuvant therapy is necessary, tissue distortion of flaps can make monitoring for recurrence difficult. Similarly, for patients in poor health or who are elderly and have substantial skin atrophy, extensive closure may be undesirable or more technically challenging with a higher risk for adverse events. In these scenarios, additional strategies are necessary to optimize wound healing and cosmesis. A cadaveric split-thickness skin graft (STSG) consisting of biologically active tissue can be used to expedite granulation.²

Technique

Following tumor clearance on the scalp (Figure 1), wide undermining is performed and 3-0 polyglactin 910 epidermal pulley sutures are placed to partially close the defect. A cadaveric STSG is placed over the remaining exposed periosteum and secured under the pulley sutures (Figure 2). The cadaveric STSG is replaced at 1-week intervals. At 4 weeks, sutures typically are removed. The cadaveric STSG is used until the exposed periosteum is fully granulated and the surgeon decides that granulation arrest is unlikely. The wound then heals by unassisted granulation. This approach provides an excellent final cosmetic outcome while avoiding extensive reconstruction (Figure 3).

Practice Implications

Scalp defects requiring closure are common for dermatologic surgeons. Several techniques to promote tissue granulation in defects that involve exposed periosteum have been reported, including (1) creation of small holes with a scalpel or chisel to access cortical circulation and (2) using laser modalities to stimulate granulation (eg, an erbium:YAG or CO₂ laser).^3,4 Although direct comparative studies are needed, the cadaveric STSG provides an approach that increases tissue granulation but does not require more invasive techniques or equipment.

Autologous STSGs need a wound bed and can fail with an exposed periosteum. Furthermore, an autologous STSG that survives may leave an unsightly, hypopigmented, depressed defect. When a defect involves the periosteum and a primary closure or flap is not ideal, a skin substitute may be an option.

Skin substitutes, including cadaveric STSG, generally are classified as bioengineered skin equivalents, amniotic tissue, or cadaveric bioproducts (Table). Unlike autologous grafts, these skin substitutes can provide rapid coverage of the defect and do not require a highly vascularized wound bed.⁶ They also minimize the inflammatory response and potentially improve the final cosmetic outcome by improving granulation rather than immediate STSG closure creating a step-off in deep wounds.⁶

Cadaveric STSGs also have been used in nonhealing ulcerations; diabetic foot ulcers; and ulcerations in which muscle, tendon, or bone are exposed, demonstrating induction of wound healing with superior scar quality and skin function.^2,7,8 The utility of the cadaveric STSG is further highlighted by its potential to reduce costs⁹ compared to bioengineered skin substitutes, though considerable variability exists in pricing (Table).

Consider using a cadaveric STSG with a guiding closure in cases in which there is concern for delayed or absent tissue granulation or when monitoring for recurrence is essential.

Cutaneous angiosarcoma (cAS) is a rare malignancy arising from vascular or lymphatic tissue. It classically presents during the sixth or seventh decades of life as a raised purple papule or plaque on the head and neck areas.¹ Primary cAS frequently mimics benign conditions, leading to delays in care. Such delays coupled with the aggressive nature of angiosarcomas leads to a poor prognosis. Five-year survival rates range from 11% to 50%, and more than half of patients die within 1 year of diagnosis.^2-7

Currently, there is no consensus on the most effective treatments, as the rare nature of cAS has made the development of controlled clinical trials difficult. Wide local excision (WLE) is most frequently employed; however, the tumor’s infiltrative growth makes complete resection and negative surgical margins difficult to achieve.⁸ Recently, Mohs micrographic surgery (MMS) has been postulated as a treatment option. The tissue-sparing nature and intraoperative margin control of MMS may provide tumor eradication and cosmesis benefits reported with other cutaneous malignancies.⁹

Nearly all localized cASs are treated with surgical excision with or without adjuvant treatment modalities; however, it is unclear which of these modalities provide a survival benefit. We conducted a systematic review of the literature to compare treatment modalities for localized cAS of the head and neck regions and to compare treatments based on tumor stage.

METHODS

A literature search was performed to identify published studies indexed by MEDLINE, Cochrane Central Register of Controlled Trials (CENTRAL), Embase, and PubMed from January 1, 1977, to May 8, 2020, reporting on cAS and treatment modalities used. The search was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines.⁵ Data extracted included patient demographics, tumor characteristics (including T1 [≤5 cm] and T2 [>5 cm and ≤10 cm] based on the American Joint Committee on Cancer soft tissue sarcoma staging criteria), treatments used, follow-up time, overall survival (OS) rates, and complications.^10,11

Studies were required to (1) include participants with head and neck cAS; (2) report original patient data following cAS treatment with surgical (WLE or MMS) and/or nonsurgical modalities (chemotherapy [CT], radiotherapy [RT], immunotherapy [IT]); (3) report outcome data related to OS rates following treatment; and (4) have articles published in English. Given the rare nature of cAS, there was no limitation on the number of participants needed.

The Newcastle-Ottawa scale for observational studies was used to assess the quality of studies.¹² Higher scores indicate low risk of bias, while lower scores represent high risk of bias.

Continuous data were reported with means and SDs, while categorical variables were reported as percentages. Overall survival means and SDs were compared between treatment modalities using an independent sample t test with P<.05 considered statistically significant. Due to the heterogeneity of the data, a meta-analysis was not reported.

RESULTS

Literature Search and Risk of Bias Assessment

There were 283 manuscripts identified, 56 articles read in full, and 40 articles included in the review (Figure). Among the 16 studies not meeting inclusion criteria, 7 did not provide enough data to isolate head and neck cAS cases,^1,13-18 6 did not report outcomes related to the current review,^19-24 and 3 did not provide enough data to isolate different treatment outcomes.^25-27 Among the included studies, 32 reported use of WLE: WLE alone (n=21)^2,7,11,28-45; WLE with RT (n=24)^{2,3,11,28-31,33-36,38-41,43-51}; WLE with CT (n=7)^{2,31,35,39,41,48,52}; WLE with RT and CT (n=11)^{2,29,31,33-35,39,40,48,52,53}; WLE with RT and IT (n=3)^35,54,55; and WLE with RT, CT, and IT (n=1).⁵³ Nine studies reported MMS: MMS alone (n=5)^39,56-59; MMS with RT (n=3)^32,50,60,61; and MMS with RT and CT (n=1).⁵¹

Risk of bias assessment identified low risk in 3 articles. High risk was identified in 5 case reports,^57-61 and 1 study did not describe patient selection.⁴³ Clayton et al⁵⁶ showed intermediate risk, given the study controlled for 1 factor.

Patient Demographics

A total of 1295 patients were included. The pooled mean age of the patients was 67.5 years (range, 3–88 years), and 64.7% were male. There were 79 cases identified as T1 and 105 as T2. A total of 825 cases were treated using WLE with or without adjuvant therapy, while a total of 9 cases were treated using MMS with and without adjuvant therapies (Table). There were 461 cases treated without surgical excision: RT alone (n=261), CT alone (n=38), IT alone (n=35), RT with CT (n=81), RT with IT (n=34), and RT with CT and IT (n=12)(Table). The median follow-up period across all studies was 23.5 months (range, 1–228 months).

Comparison Between Surgical and Nonsurgical Modalities

Wide Local Excision—Wide local excision (n=825; 63.7%) alone or in combination with other therapies was the most frequently used treatment modality. The mean (SD) OS was longest for WLE with RT, CT, and IT (n=3; 39.3 [24.1]), followed by WLE with RT (n=447; 35.9 [34.3] months), WLE with CT (n=13; 32.4 [30.2] months), WLE alone (n=324; 29.6 [34.1] months), WLE with RT and IT (n=11; 23.5 [4.9] months), and WLE with RT and CT (n=27; 20.7 [13.1] months).

Nonsurgical Modalities—Nonsurgical methods were used less frequently than surgical methods (n=461; 35.6%). The mean (SD) OS time in descending order was as follows: RT with CT and IT (n=12; 34.9 [1.2] months), RT with CT (n=81; 30.4 [37.8] months), IT alone (n=35; 25.7 [no SD reported] months), RT with IT (n=34; 20.5 [8.6] months), CT alone (n=38; 20.1 [15.9] months), and RT alone (n=261; 12.8 [8.3] months).

When comparing mean (SD) OS outcomes between surgical and nonsurgical treatment modalities, only the addition of WLE to RT significantly increased OS when compared with RT alone (WLE, 35.9 [34.3] months; RT alone, 12.8 [8.3] months; P=.001). When WLE was added to CT or both RT and CT, there was no significant difference with OS when compared with CT alone (WLE with CT, 32.4 [30.2] months; CT alone, 20.1 [15.9] months; P=.065); or both RT and CT in combination (WLE with RT and CT, 20.7 [13.1] months; RT and CT, 30.4 [37.8] months; P=.204).

Comparison Between T1 and T2 cAS

T1 Angiosarcoma—There were 79 patients identified as having T1 tumors across 16 studies.^{2,31,32,34,39-41,46,48-50,53,58-60,62} The mean (SD) OS was longest for WLE with RT, CT, and IT (n=2; 56.0 [6.0] months), followed by WLE with CT (n=4; 54.5 [41.0] months); WLE with RT (n=30; 39.7 [41.2] months); WLE alone (n=22; 37.2 [37.3] months); WLE with both RT and CT (n=7; 25.5 [18.7] months); RT with IT (n=2; 20.0 [11.0] months); RT with CT (n=6; 15.7 [6.8] months); and RT alone (n=1; 13 [no SD]) months)(eTable).

T2 Angiosarcoma—There were 105 patients with T2 tumors in 15 studies.^{2,31,32,34,39-41,46,48-50,52,53,57,62} The mean (SD) OS for each treatment modality in descending order was as follows: RT with CT and IT (n=1; 36 [no SD reported] months); RT with CT (n=23; 34.3 [46.3] months); WLE with RT (n=21; 26.3 [23.8] months); WLE with CT (n=8; 21.5 [16.6] months); WLE alone (n=16; 19.8 [15.6] months); WLE with RT and CT (n=14; 19.2 [10.5] months); RT alone (n=17; 10.1 [5.5] months); CT alone (n=2; 6.7 [3.7] months); and WLE with RT, CT, and IT (n=1; 6.0 [no SD] months)(eTable).

Mohs Micrographic Surgery—The use of MMS was only identified in case reports or small observational studies for a total of 9 patients. Five cASs were treated with MMS alone for a mean (SD) OS of 37 (21.5) months, with 4 reporting cAS staging: 2 were T1^58,59 (mean [SD] OS, 37.0 [17.0] months) and 2 were T2 tumors^39,57 (mean [SD] OS, 44.5 [26.5] months). Mohs micrographic surgery with RT was used for 3 tumors (mean [SD] OS, 34.0 [26.9] months); 2 were T1^50,60 (mean [SD] OS, 42.0 [30.0] months) and 1 unreported staging (eTable).⁵⁶ Mohs micrographic surgery with both RT and CT was used in 1 patient (unreported staging; OS, 82 months).⁵¹

Complications

Complications were rare and mainly associated with CT and RT. Four studies reported radiation dermatitis with RT.^53,55,62,63 Two studies reported peripheral neuropathy and myelotoxicity with CT.^35,51 Only 1 study reported poor wound healing due to surgical complications.²⁹

COMMENT

Cutaneous angiosarcomas are rare and have limited treatment guidelines. Surgical excision does appear to be an effective adjunct to nonsurgical treatments, particularly WLE combined with RT, CT, and IT. Although MMS ultimately may be useful for cAS, the limited number and substantial heterogeneity of reported cases precludes definitive conclusions at this time.

Achieving margin control during WLE is associated with higher OS when treating angiosarcoma,^36,46 which is particularly true for T1 tumors where margin control is imperative, and many cases are treated with a combination of WLE and RT. Overall survival times are lower for T2 tumors, as these tumors are larger and most likely have spread; therefore, more aggressive combination treatments were more prevalent. In these cases, complete margin control may be difficult to achieve and may not be as critical to the outcome if another form of adjuvant therapy can be administered promptly.^24,64

When surgery is contraindicated, RT with or without CT was the most commonly reported treatment modality. However, these treatments were notably less effective than when used in combination with surgical resection. The use of RT alone has a recurrence rate reported up to 100% in certain studies, suggesting the need to utilize RT in combination with other modalities.^23,39 It is important to note that RT often is used as monotherapy in palliative treatment, which may indirectly skew survival rates.²

Limitations of the study include a lack of randomized controlled trials. Most reports were retrospective reviews or case series, and tumor staging was sparsely reported. Finally, although MMS may provide utility in the treatment of cAS, the sample size of 9 precluded definitive conclusions from being formed about its efficacy.

CONCLUSION

Cutaneous angiosarcoma is rare and has limited data comparing different treatment modalities. The paucity of data currently limits definitive recommendations; however, both surgical and nonsurgical modalities have demonstrated potential efficacy in the treatment of cAS and may benefit from additional research. Clinicians should consider a multidisciplinary approach for patients with a diagnosis of cAS to tailor treatments on a case-by-case basis.

Cutaneous angiosarcoma (cAS) is a rare malignancy arising from vascular or lymphatic tissue. It classically presents during the sixth or seventh decades of life as a raised purple papule or plaque on the head and neck areas.¹ Primary cAS frequently mimics benign conditions, leading to delays in care. Such delays coupled with the aggressive nature of angiosarcomas leads to a poor prognosis. Five-year survival rates range from 11% to 50%, and more than half of patients die within 1 year of diagnosis.^2-7

Currently, there is no consensus on the most effective treatments, as the rare nature of cAS has made the development of controlled clinical trials difficult. Wide local excision (WLE) is most frequently employed; however, the tumor’s infiltrative growth makes complete resection and negative surgical margins difficult to achieve.⁸ Recently, Mohs micrographic surgery (MMS) has been postulated as a treatment option. The tissue-sparing nature and intraoperative margin control of MMS may provide tumor eradication and cosmesis benefits reported with other cutaneous malignancies.⁹

Nearly all localized cASs are treated with surgical excision with or without adjuvant treatment modalities; however, it is unclear which of these modalities provide a survival benefit. We conducted a systematic review of the literature to compare treatment modalities for localized cAS of the head and neck regions and to compare treatments based on tumor stage.

METHODS

A literature search was performed to identify published studies indexed by MEDLINE, Cochrane Central Register of Controlled Trials (CENTRAL), Embase, and PubMed from January 1, 1977, to May 8, 2020, reporting on cAS and treatment modalities used. The search was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines.⁵ Data extracted included patient demographics, tumor characteristics (including T1 [≤5 cm] and T2 [>5 cm and ≤10 cm] based on the American Joint Committee on Cancer soft tissue sarcoma staging criteria), treatments used, follow-up time, overall survival (OS) rates, and complications.^10,11

Studies were required to (1) include participants with head and neck cAS; (2) report original patient data following cAS treatment with surgical (WLE or MMS) and/or nonsurgical modalities (chemotherapy [CT], radiotherapy [RT], immunotherapy [IT]); (3) report outcome data related to OS rates following treatment; and (4) have articles published in English. Given the rare nature of cAS, there was no limitation on the number of participants needed.

The Newcastle-Ottawa scale for observational studies was used to assess the quality of studies.¹² Higher scores indicate low risk of bias, while lower scores represent high risk of bias.

Continuous data were reported with means and SDs, while categorical variables were reported as percentages. Overall survival means and SDs were compared between treatment modalities using an independent sample t test with P<.05 considered statistically significant. Due to the heterogeneity of the data, a meta-analysis was not reported.

RESULTS

Literature Search and Risk of Bias Assessment

There were 283 manuscripts identified, 56 articles read in full, and 40 articles included in the review (Figure). Among the 16 studies not meeting inclusion criteria, 7 did not provide enough data to isolate head and neck cAS cases,^1,13-18 6 did not report outcomes related to the current review,^19-24 and 3 did not provide enough data to isolate different treatment outcomes.^25-27 Among the included studies, 32 reported use of WLE: WLE alone (n=21)^2,7,11,28-45; WLE with RT (n=24)^{2,3,11,28-31,33-36,38-41,43-51}; WLE with CT (n=7)^{2,31,35,39,41,48,52}; WLE with RT and CT (n=11)^{2,29,31,33-35,39,40,48,52,53}; WLE with RT and IT (n=3)^35,54,55; and WLE with RT, CT, and IT (n=1).⁵³ Nine studies reported MMS: MMS alone (n=5)^39,56-59; MMS with RT (n=3)^32,50,60,61; and MMS with RT and CT (n=1).⁵¹

Risk of bias assessment identified low risk in 3 articles. High risk was identified in 5 case reports,^57-61 and 1 study did not describe patient selection.⁴³ Clayton et al⁵⁶ showed intermediate risk, given the study controlled for 1 factor.

Patient Demographics

A total of 1295 patients were included. The pooled mean age of the patients was 67.5 years (range, 3–88 years), and 64.7% were male. There were 79 cases identified as T1 and 105 as T2. A total of 825 cases were treated using WLE with or without adjuvant therapy, while a total of 9 cases were treated using MMS with and without adjuvant therapies (Table). There were 461 cases treated without surgical excision: RT alone (n=261), CT alone (n=38), IT alone (n=35), RT with CT (n=81), RT with IT (n=34), and RT with CT and IT (n=12)(Table). The median follow-up period across all studies was 23.5 months (range, 1–228 months).

Comparison Between Surgical and Nonsurgical Modalities

Wide Local Excision—Wide local excision (n=825; 63.7%) alone or in combination with other therapies was the most frequently used treatment modality. The mean (SD) OS was longest for WLE with RT, CT, and IT (n=3; 39.3 [24.1]), followed by WLE with RT (n=447; 35.9 [34.3] months), WLE with CT (n=13; 32.4 [30.2] months), WLE alone (n=324; 29.6 [34.1] months), WLE with RT and IT (n=11; 23.5 [4.9] months), and WLE with RT and CT (n=27; 20.7 [13.1] months).

Nonsurgical Modalities—Nonsurgical methods were used less frequently than surgical methods (n=461; 35.6%). The mean (SD) OS time in descending order was as follows: RT with CT and IT (n=12; 34.9 [1.2] months), RT with CT (n=81; 30.4 [37.8] months), IT alone (n=35; 25.7 [no SD reported] months), RT with IT (n=34; 20.5 [8.6] months), CT alone (n=38; 20.1 [15.9] months), and RT alone (n=261; 12.8 [8.3] months).

When comparing mean (SD) OS outcomes between surgical and nonsurgical treatment modalities, only the addition of WLE to RT significantly increased OS when compared with RT alone (WLE, 35.9 [34.3] months; RT alone, 12.8 [8.3] months; P=.001). When WLE was added to CT or both RT and CT, there was no significant difference with OS when compared with CT alone (WLE with CT, 32.4 [30.2] months; CT alone, 20.1 [15.9] months; P=.065); or both RT and CT in combination (WLE with RT and CT, 20.7 [13.1] months; RT and CT, 30.4 [37.8] months; P=.204).

Comparison Between T1 and T2 cAS

T1 Angiosarcoma—There were 79 patients identified as having T1 tumors across 16 studies.^{2,31,32,34,39-41,46,48-50,53,58-60,62} The mean (SD) OS was longest for WLE with RT, CT, and IT (n=2; 56.0 [6.0] months), followed by WLE with CT (n=4; 54.5 [41.0] months); WLE with RT (n=30; 39.7 [41.2] months); WLE alone (n=22; 37.2 [37.3] months); WLE with both RT and CT (n=7; 25.5 [18.7] months); RT with IT (n=2; 20.0 [11.0] months); RT with CT (n=6; 15.7 [6.8] months); and RT alone (n=1; 13 [no SD]) months)(eTable).

T2 Angiosarcoma—There were 105 patients with T2 tumors in 15 studies.^{2,31,32,34,39-41,46,48-50,52,53,57,62} The mean (SD) OS for each treatment modality in descending order was as follows: RT with CT and IT (n=1; 36 [no SD reported] months); RT with CT (n=23; 34.3 [46.3] months); WLE with RT (n=21; 26.3 [23.8] months); WLE with CT (n=8; 21.5 [16.6] months); WLE alone (n=16; 19.8 [15.6] months); WLE with RT and CT (n=14; 19.2 [10.5] months); RT alone (n=17; 10.1 [5.5] months); CT alone (n=2; 6.7 [3.7] months); and WLE with RT, CT, and IT (n=1; 6.0 [no SD] months)(eTable).

Mohs Micrographic Surgery—The use of MMS was only identified in case reports or small observational studies for a total of 9 patients. Five cASs were treated with MMS alone for a mean (SD) OS of 37 (21.5) months, with 4 reporting cAS staging: 2 were T1^58,59 (mean [SD] OS, 37.0 [17.0] months) and 2 were T2 tumors^39,57 (mean [SD] OS, 44.5 [26.5] months). Mohs micrographic surgery with RT was used for 3 tumors (mean [SD] OS, 34.0 [26.9] months); 2 were T1^50,60 (mean [SD] OS, 42.0 [30.0] months) and 1 unreported staging (eTable).⁵⁶ Mohs micrographic surgery with both RT and CT was used in 1 patient (unreported staging; OS, 82 months).⁵¹

Complications

Complications were rare and mainly associated with CT and RT. Four studies reported radiation dermatitis with RT.^53,55,62,63 Two studies reported peripheral neuropathy and myelotoxicity with CT.^35,51 Only 1 study reported poor wound healing due to surgical complications.²⁹

COMMENT

Cutaneous angiosarcomas are rare and have limited treatment guidelines. Surgical excision does appear to be an effective adjunct to nonsurgical treatments, particularly WLE combined with RT, CT, and IT. Although MMS ultimately may be useful for cAS, the limited number and substantial heterogeneity of reported cases precludes definitive conclusions at this time.

Achieving margin control during WLE is associated with higher OS when treating angiosarcoma,^36,46 which is particularly true for T1 tumors where margin control is imperative, and many cases are treated with a combination of WLE and RT. Overall survival times are lower for T2 tumors, as these tumors are larger and most likely have spread; therefore, more aggressive combination treatments were more prevalent. In these cases, complete margin control may be difficult to achieve and may not be as critical to the outcome if another form of adjuvant therapy can be administered promptly.^24,64

When surgery is contraindicated, RT with or without CT was the most commonly reported treatment modality. However, these treatments were notably less effective than when used in combination with surgical resection. The use of RT alone has a recurrence rate reported up to 100% in certain studies, suggesting the need to utilize RT in combination with other modalities.^23,39 It is important to note that RT often is used as monotherapy in palliative treatment, which may indirectly skew survival rates.²

Limitations of the study include a lack of randomized controlled trials. Most reports were retrospective reviews or case series, and tumor staging was sparsely reported. Finally, although MMS may provide utility in the treatment of cAS, the sample size of 9 precluded definitive conclusions from being formed about its efficacy.

CONCLUSION

Cutaneous angiosarcoma is rare and has limited data comparing different treatment modalities. The paucity of data currently limits definitive recommendations; however, both surgical and nonsurgical modalities have demonstrated potential efficacy in the treatment of cAS and may benefit from additional research. Clinicians should consider a multidisciplinary approach for patients with a diagnosis of cAS to tailor treatments on a case-by-case basis.

Cutaneous angiosarcoma (cAS) is a rare malignancy arising from vascular or lymphatic tissue. It classically presents during the sixth or seventh decades of life as a raised purple papule or plaque on the head and neck areas.¹ Primary cAS frequently mimics benign conditions, leading to delays in care. Such delays coupled with the aggressive nature of angiosarcomas leads to a poor prognosis. Five-year survival rates range from 11% to 50%, and more than half of patients die within 1 year of diagnosis.^2-7

Currently, there is no consensus on the most effective treatments, as the rare nature of cAS has made the development of controlled clinical trials difficult. Wide local excision (WLE) is most frequently employed; however, the tumor’s infiltrative growth makes complete resection and negative surgical margins difficult to achieve.⁸ Recently, Mohs micrographic surgery (MMS) has been postulated as a treatment option. The tissue-sparing nature and intraoperative margin control of MMS may provide tumor eradication and cosmesis benefits reported with other cutaneous malignancies.⁹

Nearly all localized cASs are treated with surgical excision with or without adjuvant treatment modalities; however, it is unclear which of these modalities provide a survival benefit. We conducted a systematic review of the literature to compare treatment modalities for localized cAS of the head and neck regions and to compare treatments based on tumor stage.

METHODS

A literature search was performed to identify published studies indexed by MEDLINE, Cochrane Central Register of Controlled Trials (CENTRAL), Embase, and PubMed from January 1, 1977, to May 8, 2020, reporting on cAS and treatment modalities used. The search was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines.⁵ Data extracted included patient demographics, tumor characteristics (including T1 [≤5 cm] and T2 [>5 cm and ≤10 cm] based on the American Joint Committee on Cancer soft tissue sarcoma staging criteria), treatments used, follow-up time, overall survival (OS) rates, and complications.^10,11

Studies were required to (1) include participants with head and neck cAS; (2) report original patient data following cAS treatment with surgical (WLE or MMS) and/or nonsurgical modalities (chemotherapy [CT], radiotherapy [RT], immunotherapy [IT]); (3) report outcome data related to OS rates following treatment; and (4) have articles published in English. Given the rare nature of cAS, there was no limitation on the number of participants needed.

The Newcastle-Ottawa scale for observational studies was used to assess the quality of studies.¹² Higher scores indicate low risk of bias, while lower scores represent high risk of bias.

Continuous data were reported with means and SDs, while categorical variables were reported as percentages. Overall survival means and SDs were compared between treatment modalities using an independent sample t test with P<.05 considered statistically significant. Due to the heterogeneity of the data, a meta-analysis was not reported.

RESULTS

Literature Search and Risk of Bias Assessment

There were 283 manuscripts identified, 56 articles read in full, and 40 articles included in the review (Figure). Among the 16 studies not meeting inclusion criteria, 7 did not provide enough data to isolate head and neck cAS cases,^1,13-18 6 did not report outcomes related to the current review,^19-24 and 3 did not provide enough data to isolate different treatment outcomes.^25-27 Among the included studies, 32 reported use of WLE: WLE alone (n=21)^2,7,11,28-45; WLE with RT (n=24)^{2,3,11,28-31,33-36,38-41,43-51}; WLE with CT (n=7)^{2,31,35,39,41,48,52}; WLE with RT and CT (n=11)^{2,29,31,33-35,39,40,48,52,53}; WLE with RT and IT (n=3)^35,54,55; and WLE with RT, CT, and IT (n=1).⁵³ Nine studies reported MMS: MMS alone (n=5)^39,56-59; MMS with RT (n=3)^32,50,60,61; and MMS with RT and CT (n=1).⁵¹

Risk of bias assessment identified low risk in 3 articles. High risk was identified in 5 case reports,^57-61 and 1 study did not describe patient selection.⁴³ Clayton et al⁵⁶ showed intermediate risk, given the study controlled for 1 factor.

Patient Demographics

A total of 1295 patients were included. The pooled mean age of the patients was 67.5 years (range, 3–88 years), and 64.7% were male. There were 79 cases identified as T1 and 105 as T2. A total of 825 cases were treated using WLE with or without adjuvant therapy, while a total of 9 cases were treated using MMS with and without adjuvant therapies (Table). There were 461 cases treated without surgical excision: RT alone (n=261), CT alone (n=38), IT alone (n=35), RT with CT (n=81), RT with IT (n=34), and RT with CT and IT (n=12)(Table). The median follow-up period across all studies was 23.5 months (range, 1–228 months).

Comparison Between Surgical and Nonsurgical Modalities

Wide Local Excision—Wide local excision (n=825; 63.7%) alone or in combination with other therapies was the most frequently used treatment modality. The mean (SD) OS was longest for WLE with RT, CT, and IT (n=3; 39.3 [24.1]), followed by WLE with RT (n=447; 35.9 [34.3] months), WLE with CT (n=13; 32.4 [30.2] months), WLE alone (n=324; 29.6 [34.1] months), WLE with RT and IT (n=11; 23.5 [4.9] months), and WLE with RT and CT (n=27; 20.7 [13.1] months).

Nonsurgical Modalities—Nonsurgical methods were used less frequently than surgical methods (n=461; 35.6%). The mean (SD) OS time in descending order was as follows: RT with CT and IT (n=12; 34.9 [1.2] months), RT with CT (n=81; 30.4 [37.8] months), IT alone (n=35; 25.7 [no SD reported] months), RT with IT (n=34; 20.5 [8.6] months), CT alone (n=38; 20.1 [15.9] months), and RT alone (n=261; 12.8 [8.3] months).

When comparing mean (SD) OS outcomes between surgical and nonsurgical treatment modalities, only the addition of WLE to RT significantly increased OS when compared with RT alone (WLE, 35.9 [34.3] months; RT alone, 12.8 [8.3] months; P=.001). When WLE was added to CT or both RT and CT, there was no significant difference with OS when compared with CT alone (WLE with CT, 32.4 [30.2] months; CT alone, 20.1 [15.9] months; P=.065); or both RT and CT in combination (WLE with RT and CT, 20.7 [13.1] months; RT and CT, 30.4 [37.8] months; P=.204).

Comparison Between T1 and T2 cAS

T1 Angiosarcoma—There were 79 patients identified as having T1 tumors across 16 studies.^{2,31,32,34,39-41,46,48-50,53,58-60,62} The mean (SD) OS was longest for WLE with RT, CT, and IT (n=2; 56.0 [6.0] months), followed by WLE with CT (n=4; 54.5 [41.0] months); WLE with RT (n=30; 39.7 [41.2] months); WLE alone (n=22; 37.2 [37.3] months); WLE with both RT and CT (n=7; 25.5 [18.7] months); RT with IT (n=2; 20.0 [11.0] months); RT with CT (n=6; 15.7 [6.8] months); and RT alone (n=1; 13 [no SD]) months)(eTable).

T2 Angiosarcoma—There were 105 patients with T2 tumors in 15 studies.^{2,31,32,34,39-41,46,48-50,52,53,57,62} The mean (SD) OS for each treatment modality in descending order was as follows: RT with CT and IT (n=1; 36 [no SD reported] months); RT with CT (n=23; 34.3 [46.3] months); WLE with RT (n=21; 26.3 [23.8] months); WLE with CT (n=8; 21.5 [16.6] months); WLE alone (n=16; 19.8 [15.6] months); WLE with RT and CT (n=14; 19.2 [10.5] months); RT alone (n=17; 10.1 [5.5] months); CT alone (n=2; 6.7 [3.7] months); and WLE with RT, CT, and IT (n=1; 6.0 [no SD] months)(eTable).

Mohs Micrographic Surgery—The use of MMS was only identified in case reports or small observational studies for a total of 9 patients. Five cASs were treated with MMS alone for a mean (SD) OS of 37 (21.5) months, with 4 reporting cAS staging: 2 were T1^58,59 (mean [SD] OS, 37.0 [17.0] months) and 2 were T2 tumors^39,57 (mean [SD] OS, 44.5 [26.5] months). Mohs micrographic surgery with RT was used for 3 tumors (mean [SD] OS, 34.0 [26.9] months); 2 were T1^50,60 (mean [SD] OS, 42.0 [30.0] months) and 1 unreported staging (eTable).⁵⁶ Mohs micrographic surgery with both RT and CT was used in 1 patient (unreported staging; OS, 82 months).⁵¹

Complications

Complications were rare and mainly associated with CT and RT. Four studies reported radiation dermatitis with RT.^53,55,62,63 Two studies reported peripheral neuropathy and myelotoxicity with CT.^35,51 Only 1 study reported poor wound healing due to surgical complications.²⁹

COMMENT

Cutaneous angiosarcomas are rare and have limited treatment guidelines. Surgical excision does appear to be an effective adjunct to nonsurgical treatments, particularly WLE combined with RT, CT, and IT. Although MMS ultimately may be useful for cAS, the limited number and substantial heterogeneity of reported cases precludes definitive conclusions at this time.

Achieving margin control during WLE is associated with higher OS when treating angiosarcoma,^36,46 which is particularly true for T1 tumors where margin control is imperative, and many cases are treated with a combination of WLE and RT. Overall survival times are lower for T2 tumors, as these tumors are larger and most likely have spread; therefore, more aggressive combination treatments were more prevalent. In these cases, complete margin control may be difficult to achieve and may not be as critical to the outcome if another form of adjuvant therapy can be administered promptly.^24,64

When surgery is contraindicated, RT with or without CT was the most commonly reported treatment modality. However, these treatments were notably less effective than when used in combination with surgical resection. The use of RT alone has a recurrence rate reported up to 100% in certain studies, suggesting the need to utilize RT in combination with other modalities.^23,39 It is important to note that RT often is used as monotherapy in palliative treatment, which may indirectly skew survival rates.²

Limitations of the study include a lack of randomized controlled trials. Most reports were retrospective reviews or case series, and tumor staging was sparsely reported. Finally, although MMS may provide utility in the treatment of cAS, the sample size of 9 precluded definitive conclusions from being formed about its efficacy.

CONCLUSION

Cutaneous angiosarcoma is rare and has limited data comparing different treatment modalities. The paucity of data currently limits definitive recommendations; however, both surgical and nonsurgical modalities have demonstrated potential efficacy in the treatment of cAS and may benefit from additional research. Clinicians should consider a multidisciplinary approach for patients with a diagnosis of cAS to tailor treatments on a case-by-case basis.

The Diagnosis: Dermatofibrosarcoma Protuberans

Histopathologic examination showed a dermal tumor composed of spindle cells in a storiform arrangement (Figure 1). Immunohistochemistry demonstrated positive CD34 staining of the tumoral cells (Figure 2). Clinical review, histopathologic examination, and immunohistochemistry confirmed a diagnosis of dermatofibrosarcoma protuberans (DFSP). The patient underwent Mohs micrographic surgery (MMS) with clear margins after 3 stages, followed by repair with a rotation flap. No evidence of recurrence was found at 4-year follow-up.

Dermatofibrosarcoma protuberans is a rare low-grade sarcoma of fibroblast origin with an annual incidence of 0.8 to 5 cases per million individuals.¹ It typically presents in patients aged 30 to 50 years on the trunk, scalp, or proximal extremities as an asymptomatic, flesh-colored, erythematous or brown, indurated plaque or nodule.² Due to its variable presentation, these lesions often may be misdiagnosed as lipomas or epidermoid cysts, preventing proper targeted treatment. Therefore, suspicious enlarging indurated nodules require a lower threshold for biopsy.¹

A definitive diagnosis of DFSP is achieved after a biopsy and histopathologic evaluation. Hematoxylin and eosin staining typically shows diffuse infiltration of the dermis and the subcutaneous fat by densely packed, cytologic, relatively uniform, spindle-shaped tumor cells arranged in a characteristic storiform shape. Tumor cells are spread along the septae of the subcutaneous fatty tissue.³ Immunohistochemistry is characterized by positive CD34 and negative factor XIIIa, with rare exceptions.

The differential diagnosis includes lipoma, epidermoid cyst, plexiform fibrohistiocytic tumor, and malignant peripheral nerve sheath tumor.³ Positive CD34 immunostaining, negative S-100 staining, and a storiform pattern of spindle cells can assist in differentiating DFSP from these possible differential diagnoses; lesions of these other entities are characterized by different pathologic findings. Lipomas are composed of fat tissue, epidermoid cysts have epithelial-lined cysts filled with keratin, plexiform fibrohistiocytic tumors have plexiform rays of fibrous tissue extending into fat with negative CD34 staining, and malignant peripheral nerve sheath tumors have fleshy variegated masses involving the peripheral nerve trunks with partial S-100 staining.^4-7 Additional evaluation to confirm DFSP can be accomplished by analysis of tumor samples by fluorescence in situ hybridization or reverse transcriptase–polymerase chain reaction to detect chromosomal translocations and fusion gene transcripts, as chromosomal translocations may be found in more than 90% of cases.³

Early diagnosis of DFSP is beneficial, as it can help prevent recurrence as well as metastasis. Studies have attempted to document the risk for recurrence as well as metastasis based on characteristic features and treatment strategies of DFSP. In a study of 186 patients, 3 had metastatic disease to the lungs, the most common site of metastasis.⁸ These 3 patients had fibrosarcomatous transformation within DFSP, emphasizing the importance of detailing this finding early in the diagnosis, as it was characterized by a higher degree of cellularity, cytologic atypia, mitotic activity, and negative CD34 immunostaining.⁹ In patients with suspected metastasis, lymph node ultrasonography, chest radiography, and computed tomography may be utilized.³

When treating DFSP, the goal is complete removal of the tumor with clear margins. Mohs micrographic surgery, modified MMS, and wide local excision (WLE) with 2- to 4-cm margins are appropriate treatment options, though MMS is the treatment of choice. A study comparing MMS and WLE demonstrated 3% and 30.8% recurrence rates, respectively.⁸ In MMS, complete margin evaluation on microscopy is performed after each stage to ensure negative surgical margins. The presence of positive surgical margins elicits continued resection until the margins are clear.^10,11

Other treatment modalities may be considered for patients with DFSP. Molecular therapy with imatinib, an oral tyrosine kinase inhibitor targeting platelet-derived growth factor–regulated expression, can be utilized for inoperable tumors; however, additional clinical trials are required to ensure efficacy.³ Surgical removal of the possible remaining tumor is still recommended after molecular therapy. Radiotherapy is an additional method of treatment that may be used for inoperable tumors.³

Dermatofibrosarcoma protuberans is a rare lowgrade sarcoma of fibroblast origin that typically does not metastasize but often has notable subclinical extension and recurrence. Differentiating DFSP from other tumors often may be difficult. A protuberant, flesh-colored, slowgrowing, and asymptomatic lesion often may be confused with lipomas or epidermoid cysts; therefore, biopsies with immunohistostaining for suspicious lesions is required.¹² Mohs micrographic surgery has evolved as the treatment of choice for this tumor, though WLE and new targeted molecular therapies still are considered. Proper diagnosis and treatment of DFSP is paramount in preventing future morbidity.

The Diagnosis: Dermatofibrosarcoma Protuberans

Histopathologic examination showed a dermal tumor composed of spindle cells in a storiform arrangement (Figure 1). Immunohistochemistry demonstrated positive CD34 staining of the tumoral cells (Figure 2). Clinical review, histopathologic examination, and immunohistochemistry confirmed a diagnosis of dermatofibrosarcoma protuberans (DFSP). The patient underwent Mohs micrographic surgery (MMS) with clear margins after 3 stages, followed by repair with a rotation flap. No evidence of recurrence was found at 4-year follow-up.

Dermatofibrosarcoma protuberans is a rare low-grade sarcoma of fibroblast origin with an annual incidence of 0.8 to 5 cases per million individuals.¹ It typically presents in patients aged 30 to 50 years on the trunk, scalp, or proximal extremities as an asymptomatic, flesh-colored, erythematous or brown, indurated plaque or nodule.² Due to its variable presentation, these lesions often may be misdiagnosed as lipomas or epidermoid cysts, preventing proper targeted treatment. Therefore, suspicious enlarging indurated nodules require a lower threshold for biopsy.¹

A definitive diagnosis of DFSP is achieved after a biopsy and histopathologic evaluation. Hematoxylin and eosin staining typically shows diffuse infiltration of the dermis and the subcutaneous fat by densely packed, cytologic, relatively uniform, spindle-shaped tumor cells arranged in a characteristic storiform shape. Tumor cells are spread along the septae of the subcutaneous fatty tissue.³ Immunohistochemistry is characterized by positive CD34 and negative factor XIIIa, with rare exceptions.

The differential diagnosis includes lipoma, epidermoid cyst, plexiform fibrohistiocytic tumor, and malignant peripheral nerve sheath tumor.³ Positive CD34 immunostaining, negative S-100 staining, and a storiform pattern of spindle cells can assist in differentiating DFSP from these possible differential diagnoses; lesions of these other entities are characterized by different pathologic findings. Lipomas are composed of fat tissue, epidermoid cysts have epithelial-lined cysts filled with keratin, plexiform fibrohistiocytic tumors have plexiform rays of fibrous tissue extending into fat with negative CD34 staining, and malignant peripheral nerve sheath tumors have fleshy variegated masses involving the peripheral nerve trunks with partial S-100 staining.^4-7 Additional evaluation to confirm DFSP can be accomplished by analysis of tumor samples by fluorescence in situ hybridization or reverse transcriptase–polymerase chain reaction to detect chromosomal translocations and fusion gene transcripts, as chromosomal translocations may be found in more than 90% of cases.³

Early diagnosis of DFSP is beneficial, as it can help prevent recurrence as well as metastasis. Studies have attempted to document the risk for recurrence as well as metastasis based on characteristic features and treatment strategies of DFSP. In a study of 186 patients, 3 had metastatic disease to the lungs, the most common site of metastasis.⁸ These 3 patients had fibrosarcomatous transformation within DFSP, emphasizing the importance of detailing this finding early in the diagnosis, as it was characterized by a higher degree of cellularity, cytologic atypia, mitotic activity, and negative CD34 immunostaining.⁹ In patients with suspected metastasis, lymph node ultrasonography, chest radiography, and computed tomography may be utilized.³

When treating DFSP, the goal is complete removal of the tumor with clear margins. Mohs micrographic surgery, modified MMS, and wide local excision (WLE) with 2- to 4-cm margins are appropriate treatment options, though MMS is the treatment of choice. A study comparing MMS and WLE demonstrated 3% and 30.8% recurrence rates, respectively.⁸ In MMS, complete margin evaluation on microscopy is performed after each stage to ensure negative surgical margins. The presence of positive surgical margins elicits continued resection until the margins are clear.^10,11

Other treatment modalities may be considered for patients with DFSP. Molecular therapy with imatinib, an oral tyrosine kinase inhibitor targeting platelet-derived growth factor–regulated expression, can be utilized for inoperable tumors; however, additional clinical trials are required to ensure efficacy.³ Surgical removal of the possible remaining tumor is still recommended after molecular therapy. Radiotherapy is an additional method of treatment that may be used for inoperable tumors.³

Dermatofibrosarcoma protuberans is a rare lowgrade sarcoma of fibroblast origin that typically does not metastasize but often has notable subclinical extension and recurrence. Differentiating DFSP from other tumors often may be difficult. A protuberant, flesh-colored, slowgrowing, and asymptomatic lesion often may be confused with lipomas or epidermoid cysts; therefore, biopsies with immunohistostaining for suspicious lesions is required.¹² Mohs micrographic surgery has evolved as the treatment of choice for this tumor, though WLE and new targeted molecular therapies still are considered. Proper diagnosis and treatment of DFSP is paramount in preventing future morbidity.

The Diagnosis: Dermatofibrosarcoma Protuberans

Histopathologic examination showed a dermal tumor composed of spindle cells in a storiform arrangement (Figure 1). Immunohistochemistry demonstrated positive CD34 staining of the tumoral cells (Figure 2). Clinical review, histopathologic examination, and immunohistochemistry confirmed a diagnosis of dermatofibrosarcoma protuberans (DFSP). The patient underwent Mohs micrographic surgery (MMS) with clear margins after 3 stages, followed by repair with a rotation flap. No evidence of recurrence was found at 4-year follow-up.

Dermatofibrosarcoma protuberans is a rare low-grade sarcoma of fibroblast origin with an annual incidence of 0.8 to 5 cases per million individuals.¹ It typically presents in patients aged 30 to 50 years on the trunk, scalp, or proximal extremities as an asymptomatic, flesh-colored, erythematous or brown, indurated plaque or nodule.² Due to its variable presentation, these lesions often may be misdiagnosed as lipomas or epidermoid cysts, preventing proper targeted treatment. Therefore, suspicious enlarging indurated nodules require a lower threshold for biopsy.¹

A definitive diagnosis of DFSP is achieved after a biopsy and histopathologic evaluation. Hematoxylin and eosin staining typically shows diffuse infiltration of the dermis and the subcutaneous fat by densely packed, cytologic, relatively uniform, spindle-shaped tumor cells arranged in a characteristic storiform shape. Tumor cells are spread along the septae of the subcutaneous fatty tissue.³ Immunohistochemistry is characterized by positive CD34 and negative factor XIIIa, with rare exceptions.

The differential diagnosis includes lipoma, epidermoid cyst, plexiform fibrohistiocytic tumor, and malignant peripheral nerve sheath tumor.³ Positive CD34 immunostaining, negative S-100 staining, and a storiform pattern of spindle cells can assist in differentiating DFSP from these possible differential diagnoses; lesions of these other entities are characterized by different pathologic findings. Lipomas are composed of fat tissue, epidermoid cysts have epithelial-lined cysts filled with keratin, plexiform fibrohistiocytic tumors have plexiform rays of fibrous tissue extending into fat with negative CD34 staining, and malignant peripheral nerve sheath tumors have fleshy variegated masses involving the peripheral nerve trunks with partial S-100 staining.^4-7 Additional evaluation to confirm DFSP can be accomplished by analysis of tumor samples by fluorescence in situ hybridization or reverse transcriptase–polymerase chain reaction to detect chromosomal translocations and fusion gene transcripts, as chromosomal translocations may be found in more than 90% of cases.³

Early diagnosis of DFSP is beneficial, as it can help prevent recurrence as well as metastasis. Studies have attempted to document the risk for recurrence as well as metastasis based on characteristic features and treatment strategies of DFSP. In a study of 186 patients, 3 had metastatic disease to the lungs, the most common site of metastasis.⁸ These 3 patients had fibrosarcomatous transformation within DFSP, emphasizing the importance of detailing this finding early in the diagnosis, as it was characterized by a higher degree of cellularity, cytologic atypia, mitotic activity, and negative CD34 immunostaining.⁹ In patients with suspected metastasis, lymph node ultrasonography, chest radiography, and computed tomography may be utilized.³

When treating DFSP, the goal is complete removal of the tumor with clear margins. Mohs micrographic surgery, modified MMS, and wide local excision (WLE) with 2- to 4-cm margins are appropriate treatment options, though MMS is the treatment of choice. A study comparing MMS and WLE demonstrated 3% and 30.8% recurrence rates, respectively.⁸ In MMS, complete margin evaluation on microscopy is performed after each stage to ensure negative surgical margins. The presence of positive surgical margins elicits continued resection until the margins are clear.^10,11

Other treatment modalities may be considered for patients with DFSP. Molecular therapy with imatinib, an oral tyrosine kinase inhibitor targeting platelet-derived growth factor–regulated expression, can be utilized for inoperable tumors; however, additional clinical trials are required to ensure efficacy.³ Surgical removal of the possible remaining tumor is still recommended after molecular therapy. Radiotherapy is an additional method of treatment that may be used for inoperable tumors.³

Dermatofibrosarcoma protuberans is a rare lowgrade sarcoma of fibroblast origin that typically does not metastasize but often has notable subclinical extension and recurrence. Differentiating DFSP from other tumors often may be difficult. A protuberant, flesh-colored, slowgrowing, and asymptomatic lesion often may be confused with lipomas or epidermoid cysts; therefore, biopsies with immunohistostaining for suspicious lesions is required.¹² Mohs micrographic surgery has evolved as the treatment of choice for this tumor, though WLE and new targeted molecular therapies still are considered. Proper diagnosis and treatment of DFSP is paramount in preventing future morbidity.

Clinical Challenge

An odontogenic cutaneous sinus tract (OCST) of dental origin is an uncommon occurrence and is most commonly caused by chronic periodontitis, specifically a periapical abscess due to chronic dental infection.^1,2 Odontogenic cutaneous sinus tract commonly is misdiagnosed due to a lack of symptoms on presentation, location, and variations in clinical appearance mimicking other lesions. Patients with OCSTs typically present with a fixed, erythematous, crusty, and nontender nodule with periodic drainage that easily can be mistaken for a pustule, furuncle, cyst, foreign-body lesion, squamous cell carcinoma (SCC), basal cell carcinoma, or granulomatous disorder.³ It becomes challenging for dermatologists to correctly diagnose these lesions and refer for proper evaluation and treatment.

Practice Gap

It is estimated that half of patients with an extraoral fistula are treated with multiple dermatologic surgical operations, radiotherapy, antibiotic therapy, and chemotherapy before the correct diagnosis is made.¹ Thus, proper identification of these lesions is crucial for prognosis and treatment. The most common locations for OCSTs are the mandibular, submandibular, and cervical skin.^1,2 Given these locations, patients with OCSTs commonly present to the dermatology office for evaluation. Education regarding the clinical presentation, histopathology, and proper evaluation and further referral for treatment is essential for dermatologists.

Tools and Technique for Diagnosis

We present 2 patients with OCSTs who were referred for cutaneous surgery for an SCC and epidermal cyst, but the proper diagnosis was rendered after an index of suspicion and clinicopathologic correlation led to additional testing and eventual referral for imaging.

Patient 1
A 68-year-old woman presented for Mohs micrographic surgery (MMS) of a biopsy-proven SCC on the chin. The tumor cleared after 2 MMS stages (Figure 1A). Due to notable inflammation in each stage, the slides were sent to a pathologist who confirmed clear margins. Within 2 weeks of MMS, the wound began to dehisce (Figure 1B). The patient presented 4 months later with a crusted ulcerated nodule at the MMS site (Figure 1C). A biopsy showed likely recurrence of SCC. Upon presentation to the Mohs surgeon, the nodule felt fixed to the underlying jaw, and the patient was noted to have poor dentition. The patient was sent for computed tomography (CT), which showed focal thinning of the mandible, likely postsurgical, and clear maxillary sinuses. Due to the clinical appearance and anatomic location of the lesion, a request was made for a second read of the CT, specifically looking for an OCST at the prior surgical site. With this information, the radiologist noted an OCST extending from the mandible to the lesion, reported as a periapical lucency (representing a periapical abscess) at a mandibular tooth with a dental sinus draining into the soft tissues. The patient was started on antibiotics and referred to an oral surgeon for OCST excision.

Practice Implications

Odontogenic cutaneous sinus tracts commonly are misdiagnosed due to variations in clinical presentations resembling more common cutaneous diagnoses, nonspecific histopathologic findings, and lack of dental symptoms or concerns about dentition. Clinically, an OCST presents as a fixed, red, crusty, nontender nodule with intermittent draining. With palpation of the involved area, the clinician may feel a cord of tissue connecting the skin lesion intraorally.^2,4 A clinician should have a high index of suspicion for an OCST when evaluating fixed lesions of the lower face, jawline, and neck due to the possibility of a dental origin,¹ which is important because an OCST can have similar clinical findings to lesions such as congenital fistulas, pustules, cysts, osteomyelitis, foreign-body granulomas, pyogenic granulomas, syphilis, metastatic carcinomas, basal cell carcinomas, and SCCs.^2,4 A PubMed search of articles indexed for MEDLINE using the terms Mohs, MMS, chemosurgery, odontogenic sinus, odontogenic cutaneous sinus tract, and dental sinus yielded only 2 OCSTs that were referred for MMS in the last 30 years, both of which were in the nasolabial fold/medial malar cheek.^2,4 Histopathologic findings of an OCST are nonspecific; a mixed or granulomatous inflammatory infiltrate, granulation tissue, and scarring can be seen.¹ Pseudocarcinomatous/pseudoepitheliomatous hyperplasia of the epidermis can be seen and cause histologic misinterpretation for an SCC.² Given that these findings are nonspecific without a clinical context, even with a histopathologic diagnosis of SCC or cyst, a clinical suspicion for an OCST should lead to an intraoral examination. Imaging can be ordered to look for an OCST in the area of interest. Although panoramic or periapical radiography with or without dental probes/radiopaque markers commonly have been used, more recent literature has suggested that CT may be superior to radiographs for making an OCST diagnosis.^1,3 If imaging is not consistent with the clinically suspected OCST, we recommend directly contacting the radiologist to explain the clinical history and even refresh his/her suspicion for this diagnosis.

If a diagnosis of an OCST is made, oral antibiotics can be prescribed, though the use of antibiotics has been controversial. For severe odontogenic infections, typically beta-lactam antibiotics, cephalosporins, metronidazole, clindamycin, moxifloxacin, or erythromycin can be given for 7 days or until 3 days after symptoms have resolved.⁵ Although antibiotics can bring temporary resolution, it is imperative to treat the source of infection to prevent recurrence. It is crucial for these patients to be referred to an oral surgeon for evaluation and treatment of OCST by either a root canal or tooth extraction.

Final Thoughts

We present this pearl on the diagnosis and management of an OCST, also known as a dental sinus, to better assist clinicians in making this diagnosis. With an index of suspicion as well as intraoral and radiologic evaluations, a proper diagnosis may be rendered, potentially avoiding unnecessary cutaneous surgery. In addition, we highlight the importance of communication between the clinician and the radiologist to directly look for OCST in the area of concern and consider a re-read of the images when clinical suspicion does not correlate with the radiology report.

Clinical Challenge

An odontogenic cutaneous sinus tract (OCST) of dental origin is an uncommon occurrence and is most commonly caused by chronic periodontitis, specifically a periapical abscess due to chronic dental infection.^1,2 Odontogenic cutaneous sinus tract commonly is misdiagnosed due to a lack of symptoms on presentation, location, and variations in clinical appearance mimicking other lesions. Patients with OCSTs typically present with a fixed, erythematous, crusty, and nontender nodule with periodic drainage that easily can be mistaken for a pustule, furuncle, cyst, foreign-body lesion, squamous cell carcinoma (SCC), basal cell carcinoma, or granulomatous disorder.³ It becomes challenging for dermatologists to correctly diagnose these lesions and refer for proper evaluation and treatment.

Practice Gap

It is estimated that half of patients with an extraoral fistula are treated with multiple dermatologic surgical operations, radiotherapy, antibiotic therapy, and chemotherapy before the correct diagnosis is made.¹ Thus, proper identification of these lesions is crucial for prognosis and treatment. The most common locations for OCSTs are the mandibular, submandibular, and cervical skin.^1,2 Given these locations, patients with OCSTs commonly present to the dermatology office for evaluation. Education regarding the clinical presentation, histopathology, and proper evaluation and further referral for treatment is essential for dermatologists.

Tools and Technique for Diagnosis

We present 2 patients with OCSTs who were referred for cutaneous surgery for an SCC and epidermal cyst, but the proper diagnosis was rendered after an index of suspicion and clinicopathologic correlation led to additional testing and eventual referral for imaging.

Patient 1
A 68-year-old woman presented for Mohs micrographic surgery (MMS) of a biopsy-proven SCC on the chin. The tumor cleared after 2 MMS stages (Figure 1A). Due to notable inflammation in each stage, the slides were sent to a pathologist who confirmed clear margins. Within 2 weeks of MMS, the wound began to dehisce (Figure 1B). The patient presented 4 months later with a crusted ulcerated nodule at the MMS site (Figure 1C). A biopsy showed likely recurrence of SCC. Upon presentation to the Mohs surgeon, the nodule felt fixed to the underlying jaw, and the patient was noted to have poor dentition. The patient was sent for computed tomography (CT), which showed focal thinning of the mandible, likely postsurgical, and clear maxillary sinuses. Due to the clinical appearance and anatomic location of the lesion, a request was made for a second read of the CT, specifically looking for an OCST at the prior surgical site. With this information, the radiologist noted an OCST extending from the mandible to the lesion, reported as a periapical lucency (representing a periapical abscess) at a mandibular tooth with a dental sinus draining into the soft tissues. The patient was started on antibiotics and referred to an oral surgeon for OCST excision.

Practice Implications

Odontogenic cutaneous sinus tracts commonly are misdiagnosed due to variations in clinical presentations resembling more common cutaneous diagnoses, nonspecific histopathologic findings, and lack of dental symptoms or concerns about dentition. Clinically, an OCST presents as a fixed, red, crusty, nontender nodule with intermittent draining. With palpation of the involved area, the clinician may feel a cord of tissue connecting the skin lesion intraorally.^2,4 A clinician should have a high index of suspicion for an OCST when evaluating fixed lesions of the lower face, jawline, and neck due to the possibility of a dental origin,¹ which is important because an OCST can have similar clinical findings to lesions such as congenital fistulas, pustules, cysts, osteomyelitis, foreign-body granulomas, pyogenic granulomas, syphilis, metastatic carcinomas, basal cell carcinomas, and SCCs.^2,4 A PubMed search of articles indexed for MEDLINE using the terms Mohs, MMS, chemosurgery, odontogenic sinus, odontogenic cutaneous sinus tract, and dental sinus yielded only 2 OCSTs that were referred for MMS in the last 30 years, both of which were in the nasolabial fold/medial malar cheek.^2,4 Histopathologic findings of an OCST are nonspecific; a mixed or granulomatous inflammatory infiltrate, granulation tissue, and scarring can be seen.¹ Pseudocarcinomatous/pseudoepitheliomatous hyperplasia of the epidermis can be seen and cause histologic misinterpretation for an SCC.² Given that these findings are nonspecific without a clinical context, even with a histopathologic diagnosis of SCC or cyst, a clinical suspicion for an OCST should lead to an intraoral examination. Imaging can be ordered to look for an OCST in the area of interest. Although panoramic or periapical radiography with or without dental probes/radiopaque markers commonly have been used, more recent literature has suggested that CT may be superior to radiographs for making an OCST diagnosis.^1,3 If imaging is not consistent with the clinically suspected OCST, we recommend directly contacting the radiologist to explain the clinical history and even refresh his/her suspicion for this diagnosis.

If a diagnosis of an OCST is made, oral antibiotics can be prescribed, though the use of antibiotics has been controversial. For severe odontogenic infections, typically beta-lactam antibiotics, cephalosporins, metronidazole, clindamycin, moxifloxacin, or erythromycin can be given for 7 days or until 3 days after symptoms have resolved.⁵ Although antibiotics can bring temporary resolution, it is imperative to treat the source of infection to prevent recurrence. It is crucial for these patients to be referred to an oral surgeon for evaluation and treatment of OCST by either a root canal or tooth extraction.

Final Thoughts

We present this pearl on the diagnosis and management of an OCST, also known as a dental sinus, to better assist clinicians in making this diagnosis. With an index of suspicion as well as intraoral and radiologic evaluations, a proper diagnosis may be rendered, potentially avoiding unnecessary cutaneous surgery. In addition, we highlight the importance of communication between the clinician and the radiologist to directly look for OCST in the area of concern and consider a re-read of the images when clinical suspicion does not correlate with the radiology report.

Clinical Challenge

An odontogenic cutaneous sinus tract (OCST) of dental origin is an uncommon occurrence and is most commonly caused by chronic periodontitis, specifically a periapical abscess due to chronic dental infection.^1,2 Odontogenic cutaneous sinus tract commonly is misdiagnosed due to a lack of symptoms on presentation, location, and variations in clinical appearance mimicking other lesions. Patients with OCSTs typically present with a fixed, erythematous, crusty, and nontender nodule with periodic drainage that easily can be mistaken for a pustule, furuncle, cyst, foreign-body lesion, squamous cell carcinoma (SCC), basal cell carcinoma, or granulomatous disorder.³ It becomes challenging for dermatologists to correctly diagnose these lesions and refer for proper evaluation and treatment.

Practice Gap

It is estimated that half of patients with an extraoral fistula are treated with multiple dermatologic surgical operations, radiotherapy, antibiotic therapy, and chemotherapy before the correct diagnosis is made.¹ Thus, proper identification of these lesions is crucial for prognosis and treatment. The most common locations for OCSTs are the mandibular, submandibular, and cervical skin.^1,2 Given these locations, patients with OCSTs commonly present to the dermatology office for evaluation. Education regarding the clinical presentation, histopathology, and proper evaluation and further referral for treatment is essential for dermatologists.

Tools and Technique for Diagnosis

We present 2 patients with OCSTs who were referred for cutaneous surgery for an SCC and epidermal cyst, but the proper diagnosis was rendered after an index of suspicion and clinicopathologic correlation led to additional testing and eventual referral for imaging.

Patient 1
A 68-year-old woman presented for Mohs micrographic surgery (MMS) of a biopsy-proven SCC on the chin. The tumor cleared after 2 MMS stages (Figure 1A). Due to notable inflammation in each stage, the slides were sent to a pathologist who confirmed clear margins. Within 2 weeks of MMS, the wound began to dehisce (Figure 1B). The patient presented 4 months later with a crusted ulcerated nodule at the MMS site (Figure 1C). A biopsy showed likely recurrence of SCC. Upon presentation to the Mohs surgeon, the nodule felt fixed to the underlying jaw, and the patient was noted to have poor dentition. The patient was sent for computed tomography (CT), which showed focal thinning of the mandible, likely postsurgical, and clear maxillary sinuses. Due to the clinical appearance and anatomic location of the lesion, a request was made for a second read of the CT, specifically looking for an OCST at the prior surgical site. With this information, the radiologist noted an OCST extending from the mandible to the lesion, reported as a periapical lucency (representing a periapical abscess) at a mandibular tooth with a dental sinus draining into the soft tissues. The patient was started on antibiotics and referred to an oral surgeon for OCST excision.

Practice Implications

Odontogenic cutaneous sinus tracts commonly are misdiagnosed due to variations in clinical presentations resembling more common cutaneous diagnoses, nonspecific histopathologic findings, and lack of dental symptoms or concerns about dentition. Clinically, an OCST presents as a fixed, red, crusty, nontender nodule with intermittent draining. With palpation of the involved area, the clinician may feel a cord of tissue connecting the skin lesion intraorally.^2,4 A clinician should have a high index of suspicion for an OCST when evaluating fixed lesions of the lower face, jawline, and neck due to the possibility of a dental origin,¹ which is important because an OCST can have similar clinical findings to lesions such as congenital fistulas, pustules, cysts, osteomyelitis, foreign-body granulomas, pyogenic granulomas, syphilis, metastatic carcinomas, basal cell carcinomas, and SCCs.^2,4 A PubMed search of articles indexed for MEDLINE using the terms Mohs, MMS, chemosurgery, odontogenic sinus, odontogenic cutaneous sinus tract, and dental sinus yielded only 2 OCSTs that were referred for MMS in the last 30 years, both of which were in the nasolabial fold/medial malar cheek.^2,4 Histopathologic findings of an OCST are nonspecific; a mixed or granulomatous inflammatory infiltrate, granulation tissue, and scarring can be seen.¹ Pseudocarcinomatous/pseudoepitheliomatous hyperplasia of the epidermis can be seen and cause histologic misinterpretation for an SCC.² Given that these findings are nonspecific without a clinical context, even with a histopathologic diagnosis of SCC or cyst, a clinical suspicion for an OCST should lead to an intraoral examination. Imaging can be ordered to look for an OCST in the area of interest. Although panoramic or periapical radiography with or without dental probes/radiopaque markers commonly have been used, more recent literature has suggested that CT may be superior to radiographs for making an OCST diagnosis.^1,3 If imaging is not consistent with the clinically suspected OCST, we recommend directly contacting the radiologist to explain the clinical history and even refresh his/her suspicion for this diagnosis.

If a diagnosis of an OCST is made, oral antibiotics can be prescribed, though the use of antibiotics has been controversial. For severe odontogenic infections, typically beta-lactam antibiotics, cephalosporins, metronidazole, clindamycin, moxifloxacin, or erythromycin can be given for 7 days or until 3 days after symptoms have resolved.⁵ Although antibiotics can bring temporary resolution, it is imperative to treat the source of infection to prevent recurrence. It is crucial for these patients to be referred to an oral surgeon for evaluation and treatment of OCST by either a root canal or tooth extraction.

Final Thoughts

We present this pearl on the diagnosis and management of an OCST, also known as a dental sinus, to better assist clinicians in making this diagnosis. With an index of suspicion as well as intraoral and radiologic evaluations, a proper diagnosis may be rendered, potentially avoiding unnecessary cutaneous surgery. In addition, we highlight the importance of communication between the clinician and the radiologist to directly look for OCST in the area of concern and consider a re-read of the images when clinical suspicion does not correlate with the radiology report.

A 38-year-old man sought care in the emergency department for an acute, pruritic, generalized cutaneous eruption that manifested in the intertriginous areas of the inner thighs, antecubital fossae, and axilla (FIGURE 1A). He reported associated chills, a 15-pound weight gain, and swelling of his inner thighs. Two weeks before presentation, he had received azithromycin for an upper respiratory tract infection. He was unsure if the rash developed prior to or after taking the medication. He was not taking any other medications and had no history of skin conditions.

On examination, the patient was afebrile and had bilateral thigh edema. Skin examination revealed background erythema with morbilliform papules, plaques, and patches on the bilateral flanks, back, buttocks, arms, legs, and central neck. Pinpoint pustules were present in the intertriginous sites and on the low back and buttocks. The laboratory evaluation revealed leukocytosis (11.0 × 10⁹ cells/L), increased levels of neutrophils and eosinophils, and an elevated C-reactive protein level (12.8 mg/L). The remaining laboratory results were unremarkable. The patient was referred to Dermatology.

An examination by the dermatologist 3 days later revealed small areas of annular desquamation with a few pinpoint pustules, mostly located on the inner thighs and buttocks (FIGURE 1B). Skin biopsies were taken from the anterior hip region. The histopathology revealed subacute dermatitis with mixed dermal inflammatory cells, including neutrophils and eosinophils, and discrete subcorneal spongiform pustules.

WHAT IS YOUR DIAGNOSIS?
HOW WOULD YOU TREAT THIS PATIENT?

The acute rash with minute pustules and associated leukocytosis with neutrophilia and eosinophilia led to an early diagnosis of AGEP, which may have been triggered by azithromycin—the patient’s only recent medication. AGEP is a severe cutaneous eruption that may be associated with systemic involvement. Medications are usually implicated, and patients often seek urgent evaluation.

The development of pustules on an erythematous base in intertriginous areas should raise suspicion for acute generalized exanthematous pustulosis—particularly in patients taking medication.

AGEP typically begins as an acute eruption in the intertriginous sites of the axilla, groin, and neck, but often becomes more generalized.^1,2 The diagnosis is strongly suggested by the condition’s key features: fever (97% of cases) and leukocytosis (87%) with neutrophilia (91%) and eosinophilia (30%); leukocytosis peaks 4 days after pustulosis occurs and lasts for about 12 days.¹ Although common, fever is not always documented in patients with AGEP. ³ (Our patient was a case in point.) While not a key characteristic of AGEP, our patient’s weight gain was likely explained by the severe edema secondary to his inflammatory skin eruption.

Medications are implicated, but pathophysiology is unknown

In approximately 90% of AGEP cases, medications such as antibiotics and calcium channel blockers are implicated; however, the lack of such an association does not preclude the diagnosis.^1,4 In cases of drug reactions, the eruption typically develops 1 to 2 days after a medication is begun, and the pustules typically resolve in fewer than 15 days.⁵ In 17% of patients, systemic involvement can occur and can include the liver, kidneys, bone marrow, and lungs.⁶ A physical exam, review of systems, and a laboratory evaluation can help rule out systemic involvement and guide additional testing.

AGEP has an incidence of 1 to 5 cases per million people per year, affecting women slightly more frequently than men.⁷ While the pathophysiology is not well understood, AGEP and its differential diagnoses are categorized as T cell-related inflammatory responses.^4,7

Distinguishing AGEP from some look-alikes

There are at least 4 severe cutaneous eruptions that might be confused with AGEP, all of which may be associated with fever. They include: drug reaction with eosinophilia and systemic symptoms (DRESS), also known as drug-induced hypersensitivity syndrome; Stevens-Johnson syndrome (SJS); toxic epidermal necrolysis (TEN); and pustular psoriasis.^8-10 The clinical features that may help differentiate these conditions from AGEP include timeline, mucocutaneous features, organ system involvement, and histopathologic findings.^4,8

DRESS occurs 2 to 6 weeks after drug exposure, rather than a few days, as is seen with AGEP. It often involves morbilliform erythema and facial edema with substantial eosinophilia and possible nephritis, pneumonitis, myocarditis, and thyroiditis.⁹ Unlike AGEP, DRESS does not have a predilection for intertriginous anatomic locations.

SJS and TEN occur 1 to 3 weeks after drug exposure. These conditions manifest with the development of bullae, atypical targetoid lesions, painful dusky erythema, epidermal necrosis, and mucosal involvement at multiple sites. Tubular nephritis, tracheobronchial necrosis, and multisystem organ failure can occur, with reported mortality rates of 5% to 35%.^8,11

Pustular psoriasis is frequently confused with AGEP. However, AGEP usually develops fewer than 2 days after drug exposure, with pustules that begin in intertriginous sites, and there is associated neutrophilia and possible organ involvement.^1,8 Patients who have AGEP typically do not have a history of psoriasis, while patients with pustular psoriasis often do.⁷ A history of drug reaction is uncommon with pustular psoriasis (although rapid tapering of systemic corticosteroids in patients with psoriasis can trigger the development of pustular psoriasis), whereas a previous history of drug reaction is common in AGEP.^3,7

Patients who have acute generalized exanthematous pustulosis are not likely to have a history of psoriasis.

Discontinue medication, treat with corticosteroids

Patients who have AGEP, including those with systemic involvement, generally improve after the offending drug is discontinued and treatment with topical corticosteroids is initiated.⁶ A brief course of systemic corticosteroids can also be considered for patients with severe skin involvement or systemic involvement.³

Our patient was prescribed topical corticosteroid wet dressing treatments twice daily for 2 weeks. At the 2-week follow-up visit, the rash had completely cleared, and only minimal residual erythema was noted (FIGURE 2). The patient was instructed to avoid azithromycin.

CORRESPONDENCE
David A. Wetter, MD, Department of Dermatology, Mayo Clinic, 200 First Street SW, Rochester, MN 55905; [email protected].

A 38-year-old man sought care in the emergency department for an acute, pruritic, generalized cutaneous eruption that manifested in the intertriginous areas of the inner thighs, antecubital fossae, and axilla (FIGURE 1A). He reported associated chills, a 15-pound weight gain, and swelling of his inner thighs. Two weeks before presentation, he had received azithromycin for an upper respiratory tract infection. He was unsure if the rash developed prior to or after taking the medication. He was not taking any other medications and had no history of skin conditions.

On examination, the patient was afebrile and had bilateral thigh edema. Skin examination revealed background erythema with morbilliform papules, plaques, and patches on the bilateral flanks, back, buttocks, arms, legs, and central neck. Pinpoint pustules were present in the intertriginous sites and on the low back and buttocks. The laboratory evaluation revealed leukocytosis (11.0 × 10⁹ cells/L), increased levels of neutrophils and eosinophils, and an elevated C-reactive protein level (12.8 mg/L). The remaining laboratory results were unremarkable. The patient was referred to Dermatology.

An examination by the dermatologist 3 days later revealed small areas of annular desquamation with a few pinpoint pustules, mostly located on the inner thighs and buttocks (FIGURE 1B). Skin biopsies were taken from the anterior hip region. The histopathology revealed subacute dermatitis with mixed dermal inflammatory cells, including neutrophils and eosinophils, and discrete subcorneal spongiform pustules.

WHAT IS YOUR DIAGNOSIS?
HOW WOULD YOU TREAT THIS PATIENT?

The acute rash with minute pustules and associated leukocytosis with neutrophilia and eosinophilia led to an early diagnosis of AGEP, which may have been triggered by azithromycin—the patient’s only recent medication. AGEP is a severe cutaneous eruption that may be associated with systemic involvement. Medications are usually implicated, and patients often seek urgent evaluation.

The development of pustules on an erythematous base in intertriginous areas should raise suspicion for acute generalized exanthematous pustulosis—particularly in patients taking medication.

AGEP typically begins as an acute eruption in the intertriginous sites of the axilla, groin, and neck, but often becomes more generalized.^1,2 The diagnosis is strongly suggested by the condition’s key features: fever (97% of cases) and leukocytosis (87%) with neutrophilia (91%) and eosinophilia (30%); leukocytosis peaks 4 days after pustulosis occurs and lasts for about 12 days.¹ Although common, fever is not always documented in patients with AGEP. ³ (Our patient was a case in point.) While not a key characteristic of AGEP, our patient’s weight gain was likely explained by the severe edema secondary to his inflammatory skin eruption.

Medications are implicated, but pathophysiology is unknown

In approximately 90% of AGEP cases, medications such as antibiotics and calcium channel blockers are implicated; however, the lack of such an association does not preclude the diagnosis.^1,4 In cases of drug reactions, the eruption typically develops 1 to 2 days after a medication is begun, and the pustules typically resolve in fewer than 15 days.⁵ In 17% of patients, systemic involvement can occur and can include the liver, kidneys, bone marrow, and lungs.⁶ A physical exam, review of systems, and a laboratory evaluation can help rule out systemic involvement and guide additional testing.

AGEP has an incidence of 1 to 5 cases per million people per year, affecting women slightly more frequently than men.⁷ While the pathophysiology is not well understood, AGEP and its differential diagnoses are categorized as T cell-related inflammatory responses.^4,7

Distinguishing AGEP from some look-alikes

There are at least 4 severe cutaneous eruptions that might be confused with AGEP, all of which may be associated with fever. They include: drug reaction with eosinophilia and systemic symptoms (DRESS), also known as drug-induced hypersensitivity syndrome; Stevens-Johnson syndrome (SJS); toxic epidermal necrolysis (TEN); and pustular psoriasis.^8-10 The clinical features that may help differentiate these conditions from AGEP include timeline, mucocutaneous features, organ system involvement, and histopathologic findings.^4,8

DRESS occurs 2 to 6 weeks after drug exposure, rather than a few days, as is seen with AGEP. It often involves morbilliform erythema and facial edema with substantial eosinophilia and possible nephritis, pneumonitis, myocarditis, and thyroiditis.⁹ Unlike AGEP, DRESS does not have a predilection for intertriginous anatomic locations.

SJS and TEN occur 1 to 3 weeks after drug exposure. These conditions manifest with the development of bullae, atypical targetoid lesions, painful dusky erythema, epidermal necrosis, and mucosal involvement at multiple sites. Tubular nephritis, tracheobronchial necrosis, and multisystem organ failure can occur, with reported mortality rates of 5% to 35%.^8,11

Pustular psoriasis is frequently confused with AGEP. However, AGEP usually develops fewer than 2 days after drug exposure, with pustules that begin in intertriginous sites, and there is associated neutrophilia and possible organ involvement.^1,8 Patients who have AGEP typically do not have a history of psoriasis, while patients with pustular psoriasis often do.⁷ A history of drug reaction is uncommon with pustular psoriasis (although rapid tapering of systemic corticosteroids in patients with psoriasis can trigger the development of pustular psoriasis), whereas a previous history of drug reaction is common in AGEP.^3,7

Patients who have acute generalized exanthematous pustulosis are not likely to have a history of psoriasis.

Discontinue medication, treat with corticosteroids

Patients who have AGEP, including those with systemic involvement, generally improve after the offending drug is discontinued and treatment with topical corticosteroids is initiated.⁶ A brief course of systemic corticosteroids can also be considered for patients with severe skin involvement or systemic involvement.³

Our patient was prescribed topical corticosteroid wet dressing treatments twice daily for 2 weeks. At the 2-week follow-up visit, the rash had completely cleared, and only minimal residual erythema was noted (FIGURE 2). The patient was instructed to avoid azithromycin.

CORRESPONDENCE
David A. Wetter, MD, Department of Dermatology, Mayo Clinic, 200 First Street SW, Rochester, MN 55905; [email protected].

A 38-year-old man sought care in the emergency department for an acute, pruritic, generalized cutaneous eruption that manifested in the intertriginous areas of the inner thighs, antecubital fossae, and axilla (FIGURE 1A). He reported associated chills, a 15-pound weight gain, and swelling of his inner thighs. Two weeks before presentation, he had received azithromycin for an upper respiratory tract infection. He was unsure if the rash developed prior to or after taking the medication. He was not taking any other medications and had no history of skin conditions.

On examination, the patient was afebrile and had bilateral thigh edema. Skin examination revealed background erythema with morbilliform papules, plaques, and patches on the bilateral flanks, back, buttocks, arms, legs, and central neck. Pinpoint pustules were present in the intertriginous sites and on the low back and buttocks. The laboratory evaluation revealed leukocytosis (11.0 × 10⁹ cells/L), increased levels of neutrophils and eosinophils, and an elevated C-reactive protein level (12.8 mg/L). The remaining laboratory results were unremarkable. The patient was referred to Dermatology.

An examination by the dermatologist 3 days later revealed small areas of annular desquamation with a few pinpoint pustules, mostly located on the inner thighs and buttocks (FIGURE 1B). Skin biopsies were taken from the anterior hip region. The histopathology revealed subacute dermatitis with mixed dermal inflammatory cells, including neutrophils and eosinophils, and discrete subcorneal spongiform pustules.

WHAT IS YOUR DIAGNOSIS?
HOW WOULD YOU TREAT THIS PATIENT?

The acute rash with minute pustules and associated leukocytosis with neutrophilia and eosinophilia led to an early diagnosis of AGEP, which may have been triggered by azithromycin—the patient’s only recent medication. AGEP is a severe cutaneous eruption that may be associated with systemic involvement. Medications are usually implicated, and patients often seek urgent evaluation.

The development of pustules on an erythematous base in intertriginous areas should raise suspicion for acute generalized exanthematous pustulosis—particularly in patients taking medication.

AGEP typically begins as an acute eruption in the intertriginous sites of the axilla, groin, and neck, but often becomes more generalized.^1,2 The diagnosis is strongly suggested by the condition’s key features: fever (97% of cases) and leukocytosis (87%) with neutrophilia (91%) and eosinophilia (30%); leukocytosis peaks 4 days after pustulosis occurs and lasts for about 12 days.¹ Although common, fever is not always documented in patients with AGEP. ³ (Our patient was a case in point.) While not a key characteristic of AGEP, our patient’s weight gain was likely explained by the severe edema secondary to his inflammatory skin eruption.

Medications are implicated, but pathophysiology is unknown

In approximately 90% of AGEP cases, medications such as antibiotics and calcium channel blockers are implicated; however, the lack of such an association does not preclude the diagnosis.^1,4 In cases of drug reactions, the eruption typically develops 1 to 2 days after a medication is begun, and the pustules typically resolve in fewer than 15 days.⁵ In 17% of patients, systemic involvement can occur and can include the liver, kidneys, bone marrow, and lungs.⁶ A physical exam, review of systems, and a laboratory evaluation can help rule out systemic involvement and guide additional testing.

AGEP has an incidence of 1 to 5 cases per million people per year, affecting women slightly more frequently than men.⁷ While the pathophysiology is not well understood, AGEP and its differential diagnoses are categorized as T cell-related inflammatory responses.^4,7

Distinguishing AGEP from some look-alikes

There are at least 4 severe cutaneous eruptions that might be confused with AGEP, all of which may be associated with fever. They include: drug reaction with eosinophilia and systemic symptoms (DRESS), also known as drug-induced hypersensitivity syndrome; Stevens-Johnson syndrome (SJS); toxic epidermal necrolysis (TEN); and pustular psoriasis.^8-10 The clinical features that may help differentiate these conditions from AGEP include timeline, mucocutaneous features, organ system involvement, and histopathologic findings.^4,8

DRESS occurs 2 to 6 weeks after drug exposure, rather than a few days, as is seen with AGEP. It often involves morbilliform erythema and facial edema with substantial eosinophilia and possible nephritis, pneumonitis, myocarditis, and thyroiditis.⁹ Unlike AGEP, DRESS does not have a predilection for intertriginous anatomic locations.

SJS and TEN occur 1 to 3 weeks after drug exposure. These conditions manifest with the development of bullae, atypical targetoid lesions, painful dusky erythema, epidermal necrosis, and mucosal involvement at multiple sites. Tubular nephritis, tracheobronchial necrosis, and multisystem organ failure can occur, with reported mortality rates of 5% to 35%.^8,11

Pustular psoriasis is frequently confused with AGEP. However, AGEP usually develops fewer than 2 days after drug exposure, with pustules that begin in intertriginous sites, and there is associated neutrophilia and possible organ involvement.^1,8 Patients who have AGEP typically do not have a history of psoriasis, while patients with pustular psoriasis often do.⁷ A history of drug reaction is uncommon with pustular psoriasis (although rapid tapering of systemic corticosteroids in patients with psoriasis can trigger the development of pustular psoriasis), whereas a previous history of drug reaction is common in AGEP.^3,7

Patients who have acute generalized exanthematous pustulosis are not likely to have a history of psoriasis.

Discontinue medication, treat with corticosteroids

Patients who have AGEP, including those with systemic involvement, generally improve after the offending drug is discontinued and treatment with topical corticosteroids is initiated.⁶ A brief course of systemic corticosteroids can also be considered for patients with severe skin involvement or systemic involvement.³

Our patient was prescribed topical corticosteroid wet dressing treatments twice daily for 2 weeks. At the 2-week follow-up visit, the rash had completely cleared, and only minimal residual erythema was noted (FIGURE 2). The patient was instructed to avoid azithromycin.

CORRESPONDENCE
David A. Wetter, MD, Department of Dermatology, Mayo Clinic, 200 First Street SW, Rochester, MN 55905; [email protected].