For the first time, endoscopists have used focal cryoballoon ablation to eradicate early esophageal squamous cell neoplasias, including high-grade lesions in treatment-experienced patients.

A single session of treatment with the novel, portable nitrous oxide system (C2 Therapeutics, Redwood City, Calif.) produced complete pathologic and endoscopic responses at 3 months in 8 of 10 patients, reported Marcia Irene Canto, MD, of Johns Hopkins University in Baltimore, with her associates. Two to five sessions produced complete responses in the other two patients, and all patients were disease-free at their last visit (median follow-up, 10.7 months; interquartile range, 4-14 months). The study was published online July 15 in Gastrointestinal Endoscopy (2017. doi: 10.1016/j.gie.2017.07.013).

©Nephron/Wikimedia Commons/CC BY-SA 3.0/No changes

For the first time, endoscopists have used focal cryoballoon ablation to eradicate early esophageal squamous cell neoplasias, including high-grade lesions in treatment-experienced patients.

A single session of treatment with the novel, portable nitrous oxide system (C2 Therapeutics, Redwood City, Calif.) produced complete pathologic and endoscopic responses at 3 months in 8 of 10 patients, reported Marcia Irene Canto, MD, of Johns Hopkins University in Baltimore, with her associates. Two to five sessions produced complete responses in the other two patients, and all patients were disease-free at their last visit (median follow-up, 10.7 months; interquartile range, 4-14 months). The study was published online July 15 in Gastrointestinal Endoscopy (2017. doi: 10.1016/j.gie.2017.07.013).

©Nephron/Wikimedia Commons/CC BY-SA 3.0/No changes

For the first time, endoscopists have used focal cryoballoon ablation to eradicate early esophageal squamous cell neoplasias, including high-grade lesions in treatment-experienced patients.

A single session of treatment with the novel, portable nitrous oxide system (C2 Therapeutics, Redwood City, Calif.) produced complete pathologic and endoscopic responses at 3 months in 8 of 10 patients, reported Marcia Irene Canto, MD, of Johns Hopkins University in Baltimore, with her associates. Two to five sessions produced complete responses in the other two patients, and all patients were disease-free at their last visit (median follow-up, 10.7 months; interquartile range, 4-14 months). The study was published online July 15 in Gastrointestinal Endoscopy (2017. doi: 10.1016/j.gie.2017.07.013).

©Nephron/Wikimedia Commons/CC BY-SA 3.0/No changes

Patients who received antiretroviral treatment (ART) on the day they underwent HIV testing were more likely to continue treatment and have a lower mortality rate, a study conducted in Port-au-Prince, Haiti, showed.

According to the World Health Organization, ART treatment is essential in stopping the spread of HIV; however, one-quarter to one-third of patients do not continue the treatment process after starting ART, the investigators reported.

Starting ART treatment the same day as HIV testing showed the potential to reduce this problem. “Our findings suggest that ART initiation as soon as possible after HIV testing may be beneficial for clinically stable patients,” wrote Serena Koenig, MD, of the department of infectious diseases at Brigham and Women’s Hospital, Boston, and her coinvestigators. “In resource-poor settings with fragile delivery systems, such as Haiti, the provision of immediate support by care providers at the time of HIV diagnosis can have both structural and individual impact.”

In a randomized, controlled study of 703 patients, 277 of 347 same-day ART patients (80%) retained care, and 10 (3%) died, compared with 256 of 356 patients (72%) in the standard care group, 20 (6%) of whom died (PLoS Med. 2017 Jul 25. doi: 10.1371/journal.pmed.1002357).

Retention of care was defined as attending one clinic visit between 12 months and 15 months after testing, the investigators reported.

The median age of participating patients was 37 years; the median CD4 count was 247 cells/mm³ in the standard care group and 249 cells/mm³ in the same-day group.

At the end of the study, the adjusted mortality risk among patients in the same-day ART group was less than half that of the standard care group (risk ratio, 0.43; P = .033).

Care retention might be related to a more positive mindset among those who start ART immediately after diagnosis, the investigators said.

“Making treatment initiation logistically easier for patients, we believe that same-day counseling and ART initiation increase the sense of hope, optimism, and overall connectedness to the health care system for patients, which have been shown to be important for retention,” Dr. Koenig and her colleagues wrote.

The findings update the 2016 World Health Organization standard guidelines for ART treatment, which report that there is not enough information to recommend same-day treatment. The study was limited by the single-center patient population. Patients also had lower than usual CD4 counts, which may have exaggerated successful results.

The National Institute of Allergy and Infectious Diseases funded the study. The investigators reported they had no relevant financial disclosures.

[email protected]On Twitter @eaztweets

Patients who received antiretroviral treatment (ART) on the day they underwent HIV testing were more likely to continue treatment and have a lower mortality rate, a study conducted in Port-au-Prince, Haiti, showed.

According to the World Health Organization, ART treatment is essential in stopping the spread of HIV; however, one-quarter to one-third of patients do not continue the treatment process after starting ART, the investigators reported.

Starting ART treatment the same day as HIV testing showed the potential to reduce this problem. “Our findings suggest that ART initiation as soon as possible after HIV testing may be beneficial for clinically stable patients,” wrote Serena Koenig, MD, of the department of infectious diseases at Brigham and Women’s Hospital, Boston, and her coinvestigators. “In resource-poor settings with fragile delivery systems, such as Haiti, the provision of immediate support by care providers at the time of HIV diagnosis can have both structural and individual impact.”

In a randomized, controlled study of 703 patients, 277 of 347 same-day ART patients (80%) retained care, and 10 (3%) died, compared with 256 of 356 patients (72%) in the standard care group, 20 (6%) of whom died (PLoS Med. 2017 Jul 25. doi: 10.1371/journal.pmed.1002357).

Retention of care was defined as attending one clinic visit between 12 months and 15 months after testing, the investigators reported.

The median age of participating patients was 37 years; the median CD4 count was 247 cells/mm³ in the standard care group and 249 cells/mm³ in the same-day group.

At the end of the study, the adjusted mortality risk among patients in the same-day ART group was less than half that of the standard care group (risk ratio, 0.43; P = .033).

Care retention might be related to a more positive mindset among those who start ART immediately after diagnosis, the investigators said.

“Making treatment initiation logistically easier for patients, we believe that same-day counseling and ART initiation increase the sense of hope, optimism, and overall connectedness to the health care system for patients, which have been shown to be important for retention,” Dr. Koenig and her colleagues wrote.

The findings update the 2016 World Health Organization standard guidelines for ART treatment, which report that there is not enough information to recommend same-day treatment. The study was limited by the single-center patient population. Patients also had lower than usual CD4 counts, which may have exaggerated successful results.

The National Institute of Allergy and Infectious Diseases funded the study. The investigators reported they had no relevant financial disclosures.

[email protected]On Twitter @eaztweets

Patients who received antiretroviral treatment (ART) on the day they underwent HIV testing were more likely to continue treatment and have a lower mortality rate, a study conducted in Port-au-Prince, Haiti, showed.

According to the World Health Organization, ART treatment is essential in stopping the spread of HIV; however, one-quarter to one-third of patients do not continue the treatment process after starting ART, the investigators reported.

Starting ART treatment the same day as HIV testing showed the potential to reduce this problem. “Our findings suggest that ART initiation as soon as possible after HIV testing may be beneficial for clinically stable patients,” wrote Serena Koenig, MD, of the department of infectious diseases at Brigham and Women’s Hospital, Boston, and her coinvestigators. “In resource-poor settings with fragile delivery systems, such as Haiti, the provision of immediate support by care providers at the time of HIV diagnosis can have both structural and individual impact.”

In a randomized, controlled study of 703 patients, 277 of 347 same-day ART patients (80%) retained care, and 10 (3%) died, compared with 256 of 356 patients (72%) in the standard care group, 20 (6%) of whom died (PLoS Med. 2017 Jul 25. doi: 10.1371/journal.pmed.1002357).

Retention of care was defined as attending one clinic visit between 12 months and 15 months after testing, the investigators reported.

The median age of participating patients was 37 years; the median CD4 count was 247 cells/mm³ in the standard care group and 249 cells/mm³ in the same-day group.

At the end of the study, the adjusted mortality risk among patients in the same-day ART group was less than half that of the standard care group (risk ratio, 0.43; P = .033).

Care retention might be related to a more positive mindset among those who start ART immediately after diagnosis, the investigators said.

“Making treatment initiation logistically easier for patients, we believe that same-day counseling and ART initiation increase the sense of hope, optimism, and overall connectedness to the health care system for patients, which have been shown to be important for retention,” Dr. Koenig and her colleagues wrote.

The findings update the 2016 World Health Organization standard guidelines for ART treatment, which report that there is not enough information to recommend same-day treatment. The study was limited by the single-center patient population. Patients also had lower than usual CD4 counts, which may have exaggerated successful results.

The National Institute of Allergy and Infectious Diseases funded the study. The investigators reported they had no relevant financial disclosures.

[email protected]On Twitter @eaztweets

Granuloma faciale (GF) is a chronic benign leukocytoclastic vasculitis that can be difficult to treat. It is characterized by single or multiple, soft, well-circumscribed papules, plaques, or nodules ranging in color from red, violet, or yellow to brown that may darken with sun exposure.¹ Lesions usually are smooth with follicular orifices that are accentuated, thus producing a peau d’orange appearance. Lesions generally are slow to develop and asymptomatic, though some patients report pruritus or burning.^2,3 Diagnosis of GF is based on the presence of distinct histologic features. The epidermis usually is spared, with a prominent grenz zone of normal collagen separating the epidermis from a dense infiltrate of neutrophils, lymphocytes, and eosinophils. This mixed inflammatory infiltrate is seen mainly in the superficial dermis but occasionally spreads to the lower dermis and subcutaneous tissues.⁴

As the name implies, GF usually is confined to the face but occasionally involves extrafacial sites.^5-15 The clinical characteristics of these rare extrafacial lesions are not well understood. The purpose of this study was to identify the clinical and demographic features of extrafacial GF in patients treated at Mayo Clinic (Rochester, Minnesota) during a 54-year period.

Methods

This study was approved by the Mayo institutional review board. We searched the Mayo Clinic Rochester dermatology database for all patients with a diagnosis of GF from 1959 through 2013. All histopathology slides were reviewed by a board-certified dermatologist (A.G.B.) and dermatopathologist (A.G.B.) before inclusion in this study. Histologic criteria for diagnosis of GF included the presence of a mixed inflammatory infiltrate of neutrophils, eosinophils, lymphocytes, and histiocytes in the superficial or deep dermis; a prominent grenz zone separating the uninvolved epidermis; and the presence of vascular damage, as seen by fibrin deposition in dermal blood vessels.

Medical records were reviewed for patient demographics and for history pertinent to the diagnosis of GF, including sites involved, appearance, histopathology reports, symptoms, treatments, and outcomes.

Literature Search Strategy
A computerized Ovid MEDLINE database search was undertaken to identify English-language articles concerning GF in humans using the search terms granuloma faciale with extrafacial or disseminated. To ensure that no articles were overlooked, we conducted another search for English-language articles in the Embase database (1946-2013) using the terms granuloma faciale and extrafacial or disseminated.

Statistical Analysis
Descriptive clinical and histopathologic data were summarized using means, medians, and ranges or proportions as appropriate; statistical analysis was performed using SAS software (JMP package).

Results

Ninety-six patients with a diagnosis of GF were identified, and 12 (13%) had a diagnosis of extrafacial GF. Of them, 2 patients had a diagnosis of extrafacial GF supported only by histopathology slides without accompanying clinical records and therefore were excluded from the study. Thus, 10 cases of extrafacial GF were identified from our search and were included in the study group. Clinical data for these patients are summarized in Table 1. The mean age was 58.7 years (range, 26–87 years). Six (60%) patients were male, and all patients were white. Seven patients (70%) had facial GF in addition to extrafacial GF. Six patients reported no symptoms (60%), and 4 (40%) reported pruritus, discomfort, or both associated with their GF lesions.

Extrafacial GF was diagnosed in the following anatomic locations: scalp (n=3 [30%]), posterior auricular area (n=3 [30%]), mid upper back (n=1 [10%]), right shoulder (n=1 [10%]), both ears (n=1 [10%]), right elbow (n=1 [10%]), and left infra-auricular area (n=1 [10%]). Only 1 (10%) patient had multiple extrafacial sites identified.

The lesions were characterized clinically as violet, red, and yellow to brown smooth papules, plaques, and nodules (Figure 1). Biopsies from these lesions showed a subepidermal and adnexal grenz zone; a polymorphous perivascular and periadnexal dermal infiltrate composed of neutrophils, eosinophils, lymphocytes, histiocytes, and plasma cells; and a mild subtle leukocytoclastic vasculitis with subtle mild vascular necrosis (Figure 2).

For the 9 patients who elected to undergo GF treatment, the average number of treatments attempted was 2.8 (range, 1–5). The most common method of treatment was a combination of intralesional and topical corticosteroids (n=5 [50%]). Other methods included surgery (n=3 [30%]), dapsone (n=2 [20%]), radiation therapy (n=2 [20%]), cryosurgery (n=1 [10%]), nitrogen mustard (n=1 [10%]), liquid nitrogen (n=1 [10%]), and tar shampoo and fluocinolone acetonide solution 0.01% (n=1 [10%]).

Treatment outcomes were available for 8 of 9 treated patients. Three patients (patients 7, 8, and 10) had long-term successful resolution of their lesions. Patient 7 had an extrafacial lesion that was successfully treated with intralesional and topical corticosteroids, but the facial lesions recurred. The extrafacial GF lesion in patient 8 was found adjacent to a squamous cell carcinoma and was removed with a wide surgical excision that included both lesions. Patient 10 was successfully treated with a combination of liquid nitrogen and topical corticosteroid. Patients 2 and 4 were well controlled while on dapsone; however, once the treatment was discontinued, primarily due to adverse effects, the lesions returned.

Literature Search
Our search of the English-language literature identified 20 patients with extrafacial GF (Table 2). Fifteen (75%) patients were male, which was similar to our study (6/10 [60%]). Our patient population was slightly older with a mean age of 58.7 years compared to a median age of 54 years among those identified in the literature. Additionally, 3 (30%) patients in our study had no facial lesions, as seen in classic GF, which is comparable to 8 (40%) patients identified in the literature.

Comment

Extrafacial GF primarily affects white individuals and is more prevalent in men, as demonstrated in our study. Extrafacial GF was most often found in association with facial lesions, with only 3 patients having exclusively extrafacial sites.

Data from the current study indicate that diverse modalities were used to treat extrafacial GF with variable outcomes (chronic recurrence to complete resolution). The most common first-line treatment, intralesional corticosteroid injection, was used in 5 (50%) patients but resulted in only 1 (10%) successful resolution. Other methods frequently used in our study and prior studies were surgical excision, cryotherapy, electrosurgery, and dermabrasion.^1,20 These treatments do not appear to be uniformly definitive, and the ablative methods may result in scarring.¹ Different laser treatments are emerging for the management of GF lesions. Prior reports of treating facial GF with argon and CO₂ lasers have indicated minimized residual scarring and pigmentation.^21-23 The use of pulsed dye lasers has resulted in complete clearance of facial GF lesions, without recurrence on long-term follow-up.^20,24-26

The latest investigations of immunomodulatory drugs indicate these agents are promising for the management of facial GF. Eetam et al²⁷ reported the successful use of topical tacrolimus to treat facial GF. The relatively low cost and ease of use make these topical medications a competitive alternative to currently available surgical and laser methods. The appearance of all of these novel therapeutic modalities creates the necessity for a randomized trial to establish their efficacy on extrafacial GF lesions.

The wide array of treatments reflects the recalcitrant nature of extrafacial GF lesions. Further insight into the etiology of these lesions is needed to understand their tendency to recur. The important contribution of our study is the observed predilection of extrafacial GF for sun-exposed areas such as the scalp, upper trunk, and arms and legs. This pattern of extrafacial distribution along with the lack of mucosal involvement suggests a possible connection with UV light exposure. Furthermore, one of the extrafacial GF lesions in our study occurred in association with a squamous cell carcinoma, which may be an additional indication that these sites have been subjected to sun damage. This finding strengthens the importance of obtaining an adequate skin biopsy of any well-demarcated plaque or nodule found on the trunk, arms, and legs. The observed GF prevalence on sun-exposed areas and association with photoexacerbation have been speculated in prior studies, but no clear connection has been established.^1,28

Conclusion

The findings from this study and the cases reviewed in the literature provide a unique contribution to the understanding of the clinical and demographic characteristics of extrafacial GF. The rarity of this condition is the single most important constraint of our study, reflected in the emblematic limitations of a retrospective analysis in a select group of patients. The results of analysis of data from our patients were similar to the findings reported in the English-language medical literature. Serious consideration should be given to the development of a national registry for patients with GF. A database containing the clinicopathologic features, treatments, and outcomes for patients with both facial and extrafacial manifestations of GF may be invaluable in evaluating various treatment options and increasing understanding of the etiology and epidemiology of the disease.

Granuloma faciale (GF) is a chronic benign leukocytoclastic vasculitis that can be difficult to treat. It is characterized by single or multiple, soft, well-circumscribed papules, plaques, or nodules ranging in color from red, violet, or yellow to brown that may darken with sun exposure.¹ Lesions usually are smooth with follicular orifices that are accentuated, thus producing a peau d’orange appearance. Lesions generally are slow to develop and asymptomatic, though some patients report pruritus or burning.^2,3 Diagnosis of GF is based on the presence of distinct histologic features. The epidermis usually is spared, with a prominent grenz zone of normal collagen separating the epidermis from a dense infiltrate of neutrophils, lymphocytes, and eosinophils. This mixed inflammatory infiltrate is seen mainly in the superficial dermis but occasionally spreads to the lower dermis and subcutaneous tissues.⁴

As the name implies, GF usually is confined to the face but occasionally involves extrafacial sites.^5-15 The clinical characteristics of these rare extrafacial lesions are not well understood. The purpose of this study was to identify the clinical and demographic features of extrafacial GF in patients treated at Mayo Clinic (Rochester, Minnesota) during a 54-year period.

Methods

This study was approved by the Mayo institutional review board. We searched the Mayo Clinic Rochester dermatology database for all patients with a diagnosis of GF from 1959 through 2013. All histopathology slides were reviewed by a board-certified dermatologist (A.G.B.) and dermatopathologist (A.G.B.) before inclusion in this study. Histologic criteria for diagnosis of GF included the presence of a mixed inflammatory infiltrate of neutrophils, eosinophils, lymphocytes, and histiocytes in the superficial or deep dermis; a prominent grenz zone separating the uninvolved epidermis; and the presence of vascular damage, as seen by fibrin deposition in dermal blood vessels.

Medical records were reviewed for patient demographics and for history pertinent to the diagnosis of GF, including sites involved, appearance, histopathology reports, symptoms, treatments, and outcomes.

Literature Search Strategy
A computerized Ovid MEDLINE database search was undertaken to identify English-language articles concerning GF in humans using the search terms granuloma faciale with extrafacial or disseminated. To ensure that no articles were overlooked, we conducted another search for English-language articles in the Embase database (1946-2013) using the terms granuloma faciale and extrafacial or disseminated.

Statistical Analysis
Descriptive clinical and histopathologic data were summarized using means, medians, and ranges or proportions as appropriate; statistical analysis was performed using SAS software (JMP package).

Results

Ninety-six patients with a diagnosis of GF were identified, and 12 (13%) had a diagnosis of extrafacial GF. Of them, 2 patients had a diagnosis of extrafacial GF supported only by histopathology slides without accompanying clinical records and therefore were excluded from the study. Thus, 10 cases of extrafacial GF were identified from our search and were included in the study group. Clinical data for these patients are summarized in Table 1. The mean age was 58.7 years (range, 26–87 years). Six (60%) patients were male, and all patients were white. Seven patients (70%) had facial GF in addition to extrafacial GF. Six patients reported no symptoms (60%), and 4 (40%) reported pruritus, discomfort, or both associated with their GF lesions.

Extrafacial GF was diagnosed in the following anatomic locations: scalp (n=3 [30%]), posterior auricular area (n=3 [30%]), mid upper back (n=1 [10%]), right shoulder (n=1 [10%]), both ears (n=1 [10%]), right elbow (n=1 [10%]), and left infra-auricular area (n=1 [10%]). Only 1 (10%) patient had multiple extrafacial sites identified.

The lesions were characterized clinically as violet, red, and yellow to brown smooth papules, plaques, and nodules (Figure 1). Biopsies from these lesions showed a subepidermal and adnexal grenz zone; a polymorphous perivascular and periadnexal dermal infiltrate composed of neutrophils, eosinophils, lymphocytes, histiocytes, and plasma cells; and a mild subtle leukocytoclastic vasculitis with subtle mild vascular necrosis (Figure 2).

For the 9 patients who elected to undergo GF treatment, the average number of treatments attempted was 2.8 (range, 1–5). The most common method of treatment was a combination of intralesional and topical corticosteroids (n=5 [50%]). Other methods included surgery (n=3 [30%]), dapsone (n=2 [20%]), radiation therapy (n=2 [20%]), cryosurgery (n=1 [10%]), nitrogen mustard (n=1 [10%]), liquid nitrogen (n=1 [10%]), and tar shampoo and fluocinolone acetonide solution 0.01% (n=1 [10%]).

Treatment outcomes were available for 8 of 9 treated patients. Three patients (patients 7, 8, and 10) had long-term successful resolution of their lesions. Patient 7 had an extrafacial lesion that was successfully treated with intralesional and topical corticosteroids, but the facial lesions recurred. The extrafacial GF lesion in patient 8 was found adjacent to a squamous cell carcinoma and was removed with a wide surgical excision that included both lesions. Patient 10 was successfully treated with a combination of liquid nitrogen and topical corticosteroid. Patients 2 and 4 were well controlled while on dapsone; however, once the treatment was discontinued, primarily due to adverse effects, the lesions returned.

Literature Search
Our search of the English-language literature identified 20 patients with extrafacial GF (Table 2). Fifteen (75%) patients were male, which was similar to our study (6/10 [60%]). Our patient population was slightly older with a mean age of 58.7 years compared to a median age of 54 years among those identified in the literature. Additionally, 3 (30%) patients in our study had no facial lesions, as seen in classic GF, which is comparable to 8 (40%) patients identified in the literature.

Comment

Extrafacial GF primarily affects white individuals and is more prevalent in men, as demonstrated in our study. Extrafacial GF was most often found in association with facial lesions, with only 3 patients having exclusively extrafacial sites.

Data from the current study indicate that diverse modalities were used to treat extrafacial GF with variable outcomes (chronic recurrence to complete resolution). The most common first-line treatment, intralesional corticosteroid injection, was used in 5 (50%) patients but resulted in only 1 (10%) successful resolution. Other methods frequently used in our study and prior studies were surgical excision, cryotherapy, electrosurgery, and dermabrasion.^1,20 These treatments do not appear to be uniformly definitive, and the ablative methods may result in scarring.¹ Different laser treatments are emerging for the management of GF lesions. Prior reports of treating facial GF with argon and CO₂ lasers have indicated minimized residual scarring and pigmentation.^21-23 The use of pulsed dye lasers has resulted in complete clearance of facial GF lesions, without recurrence on long-term follow-up.^20,24-26

The latest investigations of immunomodulatory drugs indicate these agents are promising for the management of facial GF. Eetam et al²⁷ reported the successful use of topical tacrolimus to treat facial GF. The relatively low cost and ease of use make these topical medications a competitive alternative to currently available surgical and laser methods. The appearance of all of these novel therapeutic modalities creates the necessity for a randomized trial to establish their efficacy on extrafacial GF lesions.

The wide array of treatments reflects the recalcitrant nature of extrafacial GF lesions. Further insight into the etiology of these lesions is needed to understand their tendency to recur. The important contribution of our study is the observed predilection of extrafacial GF for sun-exposed areas such as the scalp, upper trunk, and arms and legs. This pattern of extrafacial distribution along with the lack of mucosal involvement suggests a possible connection with UV light exposure. Furthermore, one of the extrafacial GF lesions in our study occurred in association with a squamous cell carcinoma, which may be an additional indication that these sites have been subjected to sun damage. This finding strengthens the importance of obtaining an adequate skin biopsy of any well-demarcated plaque or nodule found on the trunk, arms, and legs. The observed GF prevalence on sun-exposed areas and association with photoexacerbation have been speculated in prior studies, but no clear connection has been established.^1,28

Conclusion

The findings from this study and the cases reviewed in the literature provide a unique contribution to the understanding of the clinical and demographic characteristics of extrafacial GF. The rarity of this condition is the single most important constraint of our study, reflected in the emblematic limitations of a retrospective analysis in a select group of patients. The results of analysis of data from our patients were similar to the findings reported in the English-language medical literature. Serious consideration should be given to the development of a national registry for patients with GF. A database containing the clinicopathologic features, treatments, and outcomes for patients with both facial and extrafacial manifestations of GF may be invaluable in evaluating various treatment options and increasing understanding of the etiology and epidemiology of the disease.

Granuloma faciale (GF) is a chronic benign leukocytoclastic vasculitis that can be difficult to treat. It is characterized by single or multiple, soft, well-circumscribed papules, plaques, or nodules ranging in color from red, violet, or yellow to brown that may darken with sun exposure.¹ Lesions usually are smooth with follicular orifices that are accentuated, thus producing a peau d’orange appearance. Lesions generally are slow to develop and asymptomatic, though some patients report pruritus or burning.^2,3 Diagnosis of GF is based on the presence of distinct histologic features. The epidermis usually is spared, with a prominent grenz zone of normal collagen separating the epidermis from a dense infiltrate of neutrophils, lymphocytes, and eosinophils. This mixed inflammatory infiltrate is seen mainly in the superficial dermis but occasionally spreads to the lower dermis and subcutaneous tissues.⁴

As the name implies, GF usually is confined to the face but occasionally involves extrafacial sites.^5-15 The clinical characteristics of these rare extrafacial lesions are not well understood. The purpose of this study was to identify the clinical and demographic features of extrafacial GF in patients treated at Mayo Clinic (Rochester, Minnesota) during a 54-year period.

Methods

This study was approved by the Mayo institutional review board. We searched the Mayo Clinic Rochester dermatology database for all patients with a diagnosis of GF from 1959 through 2013. All histopathology slides were reviewed by a board-certified dermatologist (A.G.B.) and dermatopathologist (A.G.B.) before inclusion in this study. Histologic criteria for diagnosis of GF included the presence of a mixed inflammatory infiltrate of neutrophils, eosinophils, lymphocytes, and histiocytes in the superficial or deep dermis; a prominent grenz zone separating the uninvolved epidermis; and the presence of vascular damage, as seen by fibrin deposition in dermal blood vessels.

Medical records were reviewed for patient demographics and for history pertinent to the diagnosis of GF, including sites involved, appearance, histopathology reports, symptoms, treatments, and outcomes.

Literature Search Strategy
A computerized Ovid MEDLINE database search was undertaken to identify English-language articles concerning GF in humans using the search terms granuloma faciale with extrafacial or disseminated. To ensure that no articles were overlooked, we conducted another search for English-language articles in the Embase database (1946-2013) using the terms granuloma faciale and extrafacial or disseminated.

Statistical Analysis
Descriptive clinical and histopathologic data were summarized using means, medians, and ranges or proportions as appropriate; statistical analysis was performed using SAS software (JMP package).

Results

Ninety-six patients with a diagnosis of GF were identified, and 12 (13%) had a diagnosis of extrafacial GF. Of them, 2 patients had a diagnosis of extrafacial GF supported only by histopathology slides without accompanying clinical records and therefore were excluded from the study. Thus, 10 cases of extrafacial GF were identified from our search and were included in the study group. Clinical data for these patients are summarized in Table 1. The mean age was 58.7 years (range, 26–87 years). Six (60%) patients were male, and all patients were white. Seven patients (70%) had facial GF in addition to extrafacial GF. Six patients reported no symptoms (60%), and 4 (40%) reported pruritus, discomfort, or both associated with their GF lesions.

Extrafacial GF was diagnosed in the following anatomic locations: scalp (n=3 [30%]), posterior auricular area (n=3 [30%]), mid upper back (n=1 [10%]), right shoulder (n=1 [10%]), both ears (n=1 [10%]), right elbow (n=1 [10%]), and left infra-auricular area (n=1 [10%]). Only 1 (10%) patient had multiple extrafacial sites identified.

The lesions were characterized clinically as violet, red, and yellow to brown smooth papules, plaques, and nodules (Figure 1). Biopsies from these lesions showed a subepidermal and adnexal grenz zone; a polymorphous perivascular and periadnexal dermal infiltrate composed of neutrophils, eosinophils, lymphocytes, histiocytes, and plasma cells; and a mild subtle leukocytoclastic vasculitis with subtle mild vascular necrosis (Figure 2).

For the 9 patients who elected to undergo GF treatment, the average number of treatments attempted was 2.8 (range, 1–5). The most common method of treatment was a combination of intralesional and topical corticosteroids (n=5 [50%]). Other methods included surgery (n=3 [30%]), dapsone (n=2 [20%]), radiation therapy (n=2 [20%]), cryosurgery (n=1 [10%]), nitrogen mustard (n=1 [10%]), liquid nitrogen (n=1 [10%]), and tar shampoo and fluocinolone acetonide solution 0.01% (n=1 [10%]).

Treatment outcomes were available for 8 of 9 treated patients. Three patients (patients 7, 8, and 10) had long-term successful resolution of their lesions. Patient 7 had an extrafacial lesion that was successfully treated with intralesional and topical corticosteroids, but the facial lesions recurred. The extrafacial GF lesion in patient 8 was found adjacent to a squamous cell carcinoma and was removed with a wide surgical excision that included both lesions. Patient 10 was successfully treated with a combination of liquid nitrogen and topical corticosteroid. Patients 2 and 4 were well controlled while on dapsone; however, once the treatment was discontinued, primarily due to adverse effects, the lesions returned.

Literature Search
Our search of the English-language literature identified 20 patients with extrafacial GF (Table 2). Fifteen (75%) patients were male, which was similar to our study (6/10 [60%]). Our patient population was slightly older with a mean age of 58.7 years compared to a median age of 54 years among those identified in the literature. Additionally, 3 (30%) patients in our study had no facial lesions, as seen in classic GF, which is comparable to 8 (40%) patients identified in the literature.

Comment

Extrafacial GF primarily affects white individuals and is more prevalent in men, as demonstrated in our study. Extrafacial GF was most often found in association with facial lesions, with only 3 patients having exclusively extrafacial sites.

Data from the current study indicate that diverse modalities were used to treat extrafacial GF with variable outcomes (chronic recurrence to complete resolution). The most common first-line treatment, intralesional corticosteroid injection, was used in 5 (50%) patients but resulted in only 1 (10%) successful resolution. Other methods frequently used in our study and prior studies were surgical excision, cryotherapy, electrosurgery, and dermabrasion.^1,20 These treatments do not appear to be uniformly definitive, and the ablative methods may result in scarring.¹ Different laser treatments are emerging for the management of GF lesions. Prior reports of treating facial GF with argon and CO₂ lasers have indicated minimized residual scarring and pigmentation.^21-23 The use of pulsed dye lasers has resulted in complete clearance of facial GF lesions, without recurrence on long-term follow-up.^20,24-26

The latest investigations of immunomodulatory drugs indicate these agents are promising for the management of facial GF. Eetam et al²⁷ reported the successful use of topical tacrolimus to treat facial GF. The relatively low cost and ease of use make these topical medications a competitive alternative to currently available surgical and laser methods. The appearance of all of these novel therapeutic modalities creates the necessity for a randomized trial to establish their efficacy on extrafacial GF lesions.

The wide array of treatments reflects the recalcitrant nature of extrafacial GF lesions. Further insight into the etiology of these lesions is needed to understand their tendency to recur. The important contribution of our study is the observed predilection of extrafacial GF for sun-exposed areas such as the scalp, upper trunk, and arms and legs. This pattern of extrafacial distribution along with the lack of mucosal involvement suggests a possible connection with UV light exposure. Furthermore, one of the extrafacial GF lesions in our study occurred in association with a squamous cell carcinoma, which may be an additional indication that these sites have been subjected to sun damage. This finding strengthens the importance of obtaining an adequate skin biopsy of any well-demarcated plaque or nodule found on the trunk, arms, and legs. The observed GF prevalence on sun-exposed areas and association with photoexacerbation have been speculated in prior studies, but no clear connection has been established.^1,28

Conclusion

The findings from this study and the cases reviewed in the literature provide a unique contribution to the understanding of the clinical and demographic characteristics of extrafacial GF. The rarity of this condition is the single most important constraint of our study, reflected in the emblematic limitations of a retrospective analysis in a select group of patients. The results of analysis of data from our patients were similar to the findings reported in the English-language medical literature. Serious consideration should be given to the development of a national registry for patients with GF. A database containing the clinicopathologic features, treatments, and outcomes for patients with both facial and extrafacial manifestations of GF may be invaluable in evaluating various treatment options and increasing understanding of the etiology and epidemiology of the disease.

Evidence of a correlation between chronic traumatic encephalopathy (CTE) and playing American football was strengthened in the largest retrospective study cohort to date.

The progressive neurodegenerative disease associated with recurrent head trauma has been linked to football over the past decade. However, this new study took steps to solidify the connection by studying 202 deceased brains, more than double the size of a previous 2013 report.

First author Jesse Mez, MD, of Boston University, and his colleagues examined the brains donated to a brain bank jointly run by the VA Boston Healthcare System, Boston University, and the Concussion Legacy Foundation. They correlated their findings with interviews and questionnaires filled out in 2014 by those close to the donors (JAMA. 2017 Jul 25. doi: 10.1001/jama.2017.8334).

The donors were male, and a majority (79%) were white. The average age at death was 67 years. In the mild cases, there was an average of 13 years of play; in severe cases, the average was 15.8 years.

The researchers found evidence of CTE in 177 (88%) of the 202 brains of football players, with cases found in 3 (21%) who played only in high school, 48 (91%) who played in college, 9 (64%) semiprofessional players, 7 (88%) Canadian Football League players, and 110 (99%) NFL players, according to investigators.

“Nearly all of the former NFL players in this study had CTE pathology, and this pathology was frequently severe,” noted Dr. Mez and his coinvestigators. ”These findings suggest that CTE may be related to prior participation in football and that a high level of play may be related to substantial disease burden.”

Severity of CTE positively correlated with longer playing history and more competitive levels of play. According to the investigators, severe cases of CTE were found in none of the high school players, 27 college players (56%), 5 semiprofessional players (56%), 6 Canadian professional players (86%), and 95 NFL players (86%).

All participants with CTE commonly displayed certain symptoms regardless of severity level.

Impulsiveness occurred in 23 mild cases (89%) and 65 severe cases (80%). Depression was seen in 18 mild cases (67%) and 46 severe cases (56%). A total of 13 players (50%) with mild symptoms showed apathy, compared with 43 with severe symptoms (52%). Anxiety was reported for 14 mild cases (52%) and 41 severe cases (50%). Cognitive symptoms such as problems with memory and attention were also common at both levels of severity, with 19 cases (73%) and 18 cases (69%), respectively, among donors with mild CTE, and 76 (92%) and 67 (81%) among donors with severe CTE.

Those interviewed who were close to the donors also reported other behavior or mood symptoms that the investigators inferred to be related to CTE.

“Many of these participants had a substance use disorder, demonstrated suicidality, or had a family history of psychiatric illness,” the investigators wrote. “Behavior or mood symptoms may be the initial presentation for a subset of individuals with CTE, or alternatively, CTE [phosphorylated tau] pathology may lower the threshold for psychiatric manifestations in susceptible individuals.”

The investigators asserted that the correlation of CTE diagnosis and severity may be more nuanced than just how many times a player is hit.

“Several other football-related factors may influence CTE risk and disease severity, including but not limited to age at first exposure to football, duration of play, player position, cumulative hits, and linear and rotational acceleration of hits,” Dr. Mez and his associates wrote. “Recent work in living former football players has shown that age at first exposure may be related to impaired cognitive performance and altered corpus callosum white matter and that cumulative hits may be related to impairment on self-report and objective measures of cognition, mood, and behavior, although it is unclear if any of these outcomes are related to CTE pathology.”

This study was limited by the potential bias of donors who participated in the program. Researchers acknowledge that public awareness of the issue of CTE and head trauma may have influenced players with symptoms to donate their brains, thereby increasing the CTE frequency in the sample.

In addition, the brain bank where the sample was taken is not representative of the entire population of American football players, as most donors played at the college, semi-professional, and professional level, as opposed to only high school or youth leagues.

The senior author of the study, Ann C. McKee, MD, discussed the study further in a related video interview.

The National Institute of Neurological Disorders and Stroke, the National Institute of Aging, the U.S. Department of Defense, the U.S. Department of Veterans Affairs, the National Operating Committee on Standards for Athletic Equipment, the Alzheimer’s Association, the Concussion Legacy Foundation, the Andlinger Family Foundation, the WWE, and the NFL supported the study. Five authors reported receiving support from relevant sources, including the NFL.

[email protected]

On Twitter @eaztweets

Evidence of a correlation between chronic traumatic encephalopathy (CTE) and playing American football was strengthened in the largest retrospective study cohort to date.

The progressive neurodegenerative disease associated with recurrent head trauma has been linked to football over the past decade. However, this new study took steps to solidify the connection by studying 202 deceased brains, more than double the size of a previous 2013 report.

First author Jesse Mez, MD, of Boston University, and his colleagues examined the brains donated to a brain bank jointly run by the VA Boston Healthcare System, Boston University, and the Concussion Legacy Foundation. They correlated their findings with interviews and questionnaires filled out in 2014 by those close to the donors (JAMA. 2017 Jul 25. doi: 10.1001/jama.2017.8334).

The donors were male, and a majority (79%) were white. The average age at death was 67 years. In the mild cases, there was an average of 13 years of play; in severe cases, the average was 15.8 years.

The researchers found evidence of CTE in 177 (88%) of the 202 brains of football players, with cases found in 3 (21%) who played only in high school, 48 (91%) who played in college, 9 (64%) semiprofessional players, 7 (88%) Canadian Football League players, and 110 (99%) NFL players, according to investigators.

“Nearly all of the former NFL players in this study had CTE pathology, and this pathology was frequently severe,” noted Dr. Mez and his coinvestigators. ”These findings suggest that CTE may be related to prior participation in football and that a high level of play may be related to substantial disease burden.”

Severity of CTE positively correlated with longer playing history and more competitive levels of play. According to the investigators, severe cases of CTE were found in none of the high school players, 27 college players (56%), 5 semiprofessional players (56%), 6 Canadian professional players (86%), and 95 NFL players (86%).

All participants with CTE commonly displayed certain symptoms regardless of severity level.

Impulsiveness occurred in 23 mild cases (89%) and 65 severe cases (80%). Depression was seen in 18 mild cases (67%) and 46 severe cases (56%). A total of 13 players (50%) with mild symptoms showed apathy, compared with 43 with severe symptoms (52%). Anxiety was reported for 14 mild cases (52%) and 41 severe cases (50%). Cognitive symptoms such as problems with memory and attention were also common at both levels of severity, with 19 cases (73%) and 18 cases (69%), respectively, among donors with mild CTE, and 76 (92%) and 67 (81%) among donors with severe CTE.

Those interviewed who were close to the donors also reported other behavior or mood symptoms that the investigators inferred to be related to CTE.

“Many of these participants had a substance use disorder, demonstrated suicidality, or had a family history of psychiatric illness,” the investigators wrote. “Behavior or mood symptoms may be the initial presentation for a subset of individuals with CTE, or alternatively, CTE [phosphorylated tau] pathology may lower the threshold for psychiatric manifestations in susceptible individuals.”

The investigators asserted that the correlation of CTE diagnosis and severity may be more nuanced than just how many times a player is hit.

“Several other football-related factors may influence CTE risk and disease severity, including but not limited to age at first exposure to football, duration of play, player position, cumulative hits, and linear and rotational acceleration of hits,” Dr. Mez and his associates wrote. “Recent work in living former football players has shown that age at first exposure may be related to impaired cognitive performance and altered corpus callosum white matter and that cumulative hits may be related to impairment on self-report and objective measures of cognition, mood, and behavior, although it is unclear if any of these outcomes are related to CTE pathology.”

This study was limited by the potential bias of donors who participated in the program. Researchers acknowledge that public awareness of the issue of CTE and head trauma may have influenced players with symptoms to donate their brains, thereby increasing the CTE frequency in the sample.

In addition, the brain bank where the sample was taken is not representative of the entire population of American football players, as most donors played at the college, semi-professional, and professional level, as opposed to only high school or youth leagues.

The senior author of the study, Ann C. McKee, MD, discussed the study further in a related video interview.

The National Institute of Neurological Disorders and Stroke, the National Institute of Aging, the U.S. Department of Defense, the U.S. Department of Veterans Affairs, the National Operating Committee on Standards for Athletic Equipment, the Alzheimer’s Association, the Concussion Legacy Foundation, the Andlinger Family Foundation, the WWE, and the NFL supported the study. Five authors reported receiving support from relevant sources, including the NFL.

[email protected]

On Twitter @eaztweets

Evidence of a correlation between chronic traumatic encephalopathy (CTE) and playing American football was strengthened in the largest retrospective study cohort to date.

The progressive neurodegenerative disease associated with recurrent head trauma has been linked to football over the past decade. However, this new study took steps to solidify the connection by studying 202 deceased brains, more than double the size of a previous 2013 report.

First author Jesse Mez, MD, of Boston University, and his colleagues examined the brains donated to a brain bank jointly run by the VA Boston Healthcare System, Boston University, and the Concussion Legacy Foundation. They correlated their findings with interviews and questionnaires filled out in 2014 by those close to the donors (JAMA. 2017 Jul 25. doi: 10.1001/jama.2017.8334).

The donors were male, and a majority (79%) were white. The average age at death was 67 years. In the mild cases, there was an average of 13 years of play; in severe cases, the average was 15.8 years.

The researchers found evidence of CTE in 177 (88%) of the 202 brains of football players, with cases found in 3 (21%) who played only in high school, 48 (91%) who played in college, 9 (64%) semiprofessional players, 7 (88%) Canadian Football League players, and 110 (99%) NFL players, according to investigators.

“Nearly all of the former NFL players in this study had CTE pathology, and this pathology was frequently severe,” noted Dr. Mez and his coinvestigators. ”These findings suggest that CTE may be related to prior participation in football and that a high level of play may be related to substantial disease burden.”

Severity of CTE positively correlated with longer playing history and more competitive levels of play. According to the investigators, severe cases of CTE were found in none of the high school players, 27 college players (56%), 5 semiprofessional players (56%), 6 Canadian professional players (86%), and 95 NFL players (86%).

All participants with CTE commonly displayed certain symptoms regardless of severity level.

Impulsiveness occurred in 23 mild cases (89%) and 65 severe cases (80%). Depression was seen in 18 mild cases (67%) and 46 severe cases (56%). A total of 13 players (50%) with mild symptoms showed apathy, compared with 43 with severe symptoms (52%). Anxiety was reported for 14 mild cases (52%) and 41 severe cases (50%). Cognitive symptoms such as problems with memory and attention were also common at both levels of severity, with 19 cases (73%) and 18 cases (69%), respectively, among donors with mild CTE, and 76 (92%) and 67 (81%) among donors with severe CTE.

Those interviewed who were close to the donors also reported other behavior or mood symptoms that the investigators inferred to be related to CTE.

“Many of these participants had a substance use disorder, demonstrated suicidality, or had a family history of psychiatric illness,” the investigators wrote. “Behavior or mood symptoms may be the initial presentation for a subset of individuals with CTE, or alternatively, CTE [phosphorylated tau] pathology may lower the threshold for psychiatric manifestations in susceptible individuals.”

The investigators asserted that the correlation of CTE diagnosis and severity may be more nuanced than just how many times a player is hit.

“Several other football-related factors may influence CTE risk and disease severity, including but not limited to age at first exposure to football, duration of play, player position, cumulative hits, and linear and rotational acceleration of hits,” Dr. Mez and his associates wrote. “Recent work in living former football players has shown that age at first exposure may be related to impaired cognitive performance and altered corpus callosum white matter and that cumulative hits may be related to impairment on self-report and objective measures of cognition, mood, and behavior, although it is unclear if any of these outcomes are related to CTE pathology.”

This study was limited by the potential bias of donors who participated in the program. Researchers acknowledge that public awareness of the issue of CTE and head trauma may have influenced players with symptoms to donate their brains, thereby increasing the CTE frequency in the sample.

In addition, the brain bank where the sample was taken is not representative of the entire population of American football players, as most donors played at the college, semi-professional, and professional level, as opposed to only high school or youth leagues.

The senior author of the study, Ann C. McKee, MD, discussed the study further in a related video interview.

The National Institute of Neurological Disorders and Stroke, the National Institute of Aging, the U.S. Department of Defense, the U.S. Department of Veterans Affairs, the National Operating Committee on Standards for Athletic Equipment, the Alzheimer’s Association, the Concussion Legacy Foundation, the Andlinger Family Foundation, the WWE, and the NFL supported the study. Five authors reported receiving support from relevant sources, including the NFL.

[email protected]

On Twitter @eaztweets

Mobile health interventions targeting mothers of healthy newborns significantly improved safe sleep practices, compared with controls, in a randomized trial of 1,600 mothers published online July 25 in JAMA.

Despite the success of the Back to Sleep campaign in reducing rates of sudden infant death syndrome, approximately 3,500 infant deaths due to SIDS, accidental suffocation, or strangulation in bed occurred in 2014, wrote Rachel Y. Moon, MD, of the University of Virginia, Charlottesville, and her colleagues (JAMA. 2017;318:351-9).

Halfpoint/thinkstock

Mobile health interventions targeting mothers of healthy newborns significantly improved safe sleep practices, compared with controls, in a randomized trial of 1,600 mothers published online July 25 in JAMA.

Despite the success of the Back to Sleep campaign in reducing rates of sudden infant death syndrome, approximately 3,500 infant deaths due to SIDS, accidental suffocation, or strangulation in bed occurred in 2014, wrote Rachel Y. Moon, MD, of the University of Virginia, Charlottesville, and her colleagues (JAMA. 2017;318:351-9).

Halfpoint/thinkstock

Mobile health interventions targeting mothers of healthy newborns significantly improved safe sleep practices, compared with controls, in a randomized trial of 1,600 mothers published online July 25 in JAMA.

Despite the success of the Back to Sleep campaign in reducing rates of sudden infant death syndrome, approximately 3,500 infant deaths due to SIDS, accidental suffocation, or strangulation in bed occurred in 2014, wrote Rachel Y. Moon, MD, of the University of Virginia, Charlottesville, and her colleagues (JAMA. 2017;318:351-9).

Halfpoint/thinkstock

SAN FRANCISCO – Very brief, outside-the-box therapeutic interventions are racking up respectable efficacy scores in randomized, controlled trials addressing a variety of common psychiatric problems in youths, Jessica L. Schleider observed at the annual conference of the Anxiety and Depression Association of America.

The impetus for developing very brief interventions – or VBIs, as they are known in psychotherapy research parlance – is mounting recognition that conventional treatment approaches have by and large failed children and adolescents who have mental health problems, explained Ms. Schleider, a doctoral candidate in clinical psychology at Harvard University in Cambridge, Mass.

Bruce Jancin/Frontline Medical News

[email protected]

SAN FRANCISCO – Very brief, outside-the-box therapeutic interventions are racking up respectable efficacy scores in randomized, controlled trials addressing a variety of common psychiatric problems in youths, Jessica L. Schleider observed at the annual conference of the Anxiety and Depression Association of America.

The impetus for developing very brief interventions – or VBIs, as they are known in psychotherapy research parlance – is mounting recognition that conventional treatment approaches have by and large failed children and adolescents who have mental health problems, explained Ms. Schleider, a doctoral candidate in clinical psychology at Harvard University in Cambridge, Mass.

Bruce Jancin/Frontline Medical News

[email protected]

SAN FRANCISCO – Very brief, outside-the-box therapeutic interventions are racking up respectable efficacy scores in randomized, controlled trials addressing a variety of common psychiatric problems in youths, Jessica L. Schleider observed at the annual conference of the Anxiety and Depression Association of America.

The impetus for developing very brief interventions – or VBIs, as they are known in psychotherapy research parlance – is mounting recognition that conventional treatment approaches have by and large failed children and adolescents who have mental health problems, explained Ms. Schleider, a doctoral candidate in clinical psychology at Harvard University in Cambridge, Mass.

Bruce Jancin/Frontline Medical News

[email protected]

CHICAGO – Ask patients with recessive dystrophic epidermolysis bullosa (EB) to name their most bothersome symptom, and they’re likely to say itch, followed closely by pain, according to Jemima Mellerio, MD.

“We don’t really understand a lot about the mechanism of itch in patients with this disease, which is one of the reasons why we don’t have good treatments,” Prof. Mellerio said at the World Congress of Pediatric Dermatology.

[email protected]

CHICAGO – Ask patients with recessive dystrophic epidermolysis bullosa (EB) to name their most bothersome symptom, and they’re likely to say itch, followed closely by pain, according to Jemima Mellerio, MD.

“We don’t really understand a lot about the mechanism of itch in patients with this disease, which is one of the reasons why we don’t have good treatments,” Prof. Mellerio said at the World Congress of Pediatric Dermatology.

[email protected]

CHICAGO – Ask patients with recessive dystrophic epidermolysis bullosa (EB) to name their most bothersome symptom, and they’re likely to say itch, followed closely by pain, according to Jemima Mellerio, MD.

“We don’t really understand a lot about the mechanism of itch in patients with this disease, which is one of the reasons why we don’t have good treatments,” Prof. Mellerio said at the World Congress of Pediatric Dermatology.

[email protected]

Case Report

A 37-year-old woman was admitted to the intensive care unit secondary to the acute development of an erythematous rash with tissue sloughing that involved acral sites and mucosal surfaces. Her medical history was notable for anti-Ro/Sjögren syndrome antigen A (SS-A)–positive lupus erythematosus (LE) with a morphologic semblance to subacute cutaneous LE (SCLE). Prior treatment had included oral corticosteroids. In addition, she reported a concurrent history of acral and mucosal lesions that appeared to flare with her lupus. The nature of these lesions was not clear to the patient or her physicians. Before this particular episode, her primary care physician had attempted to wean her off of the corticosteroids. As she dropped below 20 mg of prednisone daily, new lesions developed. The patient stated that her social situation was poor and that these lesions did seem to develop more frequently during times of physical and emotional stress. She recounted her first episode developing during her second pregnancy. Oral prednisone and over-the-counter calcium with vitamin D were her only reported medications. She denied the use of any other medications, including nonsteroidal anti-inflammatory drugs, acetaminophen, and recent antibiotic therapy.

Dermatology was called in for consultation, and physical examination revealed areas of epidermal sloughing on the hands and feet. Complete clinical exposure of the underlying dermis was noted with remarkable tenderness. These lesions were noted to be in various stages of healing (Figure 1). Figure 2 displays a lesion in early development. The mucosal surfaces of the lips and eyes demonstrated hemorrhagic crusting, and some tissue sloughing was noted on the ears. A widespread erythematous exanthema with fine scaling was noted on the face, neck, chest, back, abdomen, arms, and legs (Figure 3).

Laboratory evaluation revealed positive antinuclear antibodies (ANAs), anti-Ro/SS-A antibodies, anti-La/Sjögren syndrome antigen B (SS-B) antibodies, and anti–double-stranded DNA. The hemoglobin level was 9.4 g/dL (reference range, 12–15 g/dL) and hematocrit was 28.8% (reference range, 36%–47%). The mean corpuscular hemoglobin level was 32 pg/cell (reference range, 27–31 pg/cell), and the mean corpuscular hemoglobin concentration was 32.5 g/dL (reference range, 30–35 g/dL). Rheumatoid factor (RF) and herpes simplex virus types 1 and 2 IgM were all found to be negative.

A deep shave biopsy obtained from the patient’s right knee revealed an atrophic interface dermatitis associated with a lymphocytic eccrine hidradenitis accompanied by abundant mesenchymal mucin deposition (Figure 4). Direct immunofluorescence (DIF) from the same area demonstrated IgG and IgM along the dermoepidermal junction with some granular deposition. Frozen sections performed on acral lesions demonstrated epidermal necrosis (Figure 5). Direct immunofluorescence of acral lesions was negative. In light of these findings, a diagnosis of Rowell syndrome (RS) was suspected to be the most likely explanation for the presentation.

Intravenous corticosteroids and antibiotics were administered, and over a 2-week hospitalization, the lesions on the feet and hands slowly reepithelialized. Physical therapy was required to aid in ambulation. The patient was discharged on a tapering course of oral prednisone and hydroxychloroquine. After 6 months of therapy with hydroxychloroquine 200 mg twice daily, the patient continued to experience recurrent bouts of acral lesions, and pulse doses of oral prednisone were required. The lesions currently are controlled with azathioprine 50 mg twice daily and prednisone 10 mg by mouth daily.

Comment

The 4 prototypical patients identified by Rowell et al¹ in 1963 in the first account of the eponymous syndrome were all females with discoid lupus erythematosus (DLE) and perniosis. In addition, they all displayed positive RF and saline extract of human tissue antibodies (analogous to anti-Ro/SS-A and anti-La/SS-B).² Since then, at least 132 patients with clinical symptoms suspicious of RS have been identified with variations on these original criteria.³ The reported permutations of the lupus component of the disease include cutaneous LE (CLE), bullous systemic LE, necrotic lesions associated with antiphospholipid syndrome, annular/polycyclic SCLE, systemic LE (SLE) without CLE, SLE with lupus nephritis, SLE with pericarditis, SLE with systemic vasculitis, Sjögren syndrome, rheumatoid arthritis, and necrotizing lymphadenitis.² In addition, variations of the erythema multiforme (EM)–like lesions found in reported cases include changes to their gross appearance (flat vs raised), location (acral or mucosal involvement), and resemblance to other conditions (Stevens-Johnson syndrome or toxic epidermal necrolysis).^2,3 From this information alone, it is clear that, as further cases have been chronicled, defining exact criteria for the disease has been challenging.

The essential question concerning the existence of RS hinges on the strength of its distinctiveness: Is it a unique disorder or merely another variant of lupus? Antiga et al² concluded that it should be characterized as a variant of SCLE. Lee at al⁴ agreed, stating that “[i]n view of the lack of specific features that distinguish RS from LE, Kuhn et al⁵ suggested that [RS] is probably not a distinct entity and is now widely considered to be a variant of SCLE.” One of the primary contributors to this conclusion is that the laboratory findings of reported patients with SCLE have more closely mirrored the original cases from Rowell et al’s¹ report than those of typical LE. Patients with SCLE have demonstrated positive ANA antibodies in 60% to 80% of cases, positive anti-Ro/SS-A antibodies in 40% to 100% of cases, positive anti-La/SS-B antibodies in 12% to 42% of cases, positive anti–double-stranded DNA in 1.2% to 10% of cases, and positive RF antibodies in 33% of cases.² An argument could certainly be made to ascribe our patient’s condition to an SCLE variant, as 4 of 5 preceding laboratory findings were found to be positive; however, the majority of reported cases of SCLE have been linked to drugs (ie, hydrochlorothiazide, angiotensin-converting enzyme inhibitors, calcium channel blockers, terbinafine),² which has not commonly been the attributable etiology of other cases of RS, including the 4 cases reported by Rowell et al.¹

In a review of the literature on RS since 2010 in addition to their report of 132 new cases, Torchia et al³ outlined a set of diagnostic standards for the condition consisting of major and minor criteria. According to the authors, if all 4 major and 1 minor criteria are met, the patient meets the standards for true RS. The major criteria include the following: (1) presence of chronic CLE [DLE and/or chilblain]; (2) presence of EM-like lesions [typical or atypical targets]; (3) at least 1 positivity among speckled ANA, anti-Ro/SS-A, and anti-La/SS-B antibodies; and (4) negative DIF on lesional EM-like targetoid lesions. The minor criteria include the following: (1) absence of infectious or pharmacologic triggers; (2) absence of typical EM location (acral and mucosal); and (3) presence of at least 1 additional American College of Rheumatology criterion for diagnosis of SLE⁸ besides discoid rash and positive ANA antibodies and excluding photosensitivity, malar rash, and oral ulcers. Using these criteria, the patient in our case met the standards for diagnosis of RS.

One area of disagreement that has been encountered in the literature is the exact histologic determination of true RS, specifically related to the microscopic findings of the EM-like lesions. Two cases presented by Modi et al⁶ were interpreted under the stipulation that true RS must contain histologic LE and histologic EM. Because the EM-appearing lesions revealed LE histology, the cases were concluded to be variants of LE. These cases are similar to our case in that the EM-like lesions in our patient demonstrated LE pathology. Torchia et al,³ as demonstrated in the above criteria, seemed to be less concerned about the histology of the EM-like lesions, only requiring them to show negative DIF.

Conclusion

In the search for answers concerning RS, many unanswered questions remain: Where should the line be drawn in the inclusion of so many variations of both the LE and EM components of the condition? Also, should these elements even be approached as distinct components in the first place? Viewing the majority of RS cases as simply simultaneous LE and EM, Shteyngarts et al⁷ concluded that “the concomitant occurrence of EM with LE did not change the course, therapy, or prognosis of either disease. SLE and DLE can coexist with EM, but the coexistence does not impart any unusual characteristic to either illness. Rowell’s syndrome is not reproducible, and the immunologic disturbances in such patients are probably coincidental.”

If the condition is a genuine pathological individuality, should we not view the seemingly separate LE and EM as the product of a single underlying biochemical process? These questions and others in the search for a true definition of the disease should continue to be debated. It is clear that further investigation is warranted in the understanding of the underlying mechanism of the pathology.

Case Report

A 37-year-old woman was admitted to the intensive care unit secondary to the acute development of an erythematous rash with tissue sloughing that involved acral sites and mucosal surfaces. Her medical history was notable for anti-Ro/Sjögren syndrome antigen A (SS-A)–positive lupus erythematosus (LE) with a morphologic semblance to subacute cutaneous LE (SCLE). Prior treatment had included oral corticosteroids. In addition, she reported a concurrent history of acral and mucosal lesions that appeared to flare with her lupus. The nature of these lesions was not clear to the patient or her physicians. Before this particular episode, her primary care physician had attempted to wean her off of the corticosteroids. As she dropped below 20 mg of prednisone daily, new lesions developed. The patient stated that her social situation was poor and that these lesions did seem to develop more frequently during times of physical and emotional stress. She recounted her first episode developing during her second pregnancy. Oral prednisone and over-the-counter calcium with vitamin D were her only reported medications. She denied the use of any other medications, including nonsteroidal anti-inflammatory drugs, acetaminophen, and recent antibiotic therapy.

Dermatology was called in for consultation, and physical examination revealed areas of epidermal sloughing on the hands and feet. Complete clinical exposure of the underlying dermis was noted with remarkable tenderness. These lesions were noted to be in various stages of healing (Figure 1). Figure 2 displays a lesion in early development. The mucosal surfaces of the lips and eyes demonstrated hemorrhagic crusting, and some tissue sloughing was noted on the ears. A widespread erythematous exanthema with fine scaling was noted on the face, neck, chest, back, abdomen, arms, and legs (Figure 3).

Laboratory evaluation revealed positive antinuclear antibodies (ANAs), anti-Ro/SS-A antibodies, anti-La/Sjögren syndrome antigen B (SS-B) antibodies, and anti–double-stranded DNA. The hemoglobin level was 9.4 g/dL (reference range, 12–15 g/dL) and hematocrit was 28.8% (reference range, 36%–47%). The mean corpuscular hemoglobin level was 32 pg/cell (reference range, 27–31 pg/cell), and the mean corpuscular hemoglobin concentration was 32.5 g/dL (reference range, 30–35 g/dL). Rheumatoid factor (RF) and herpes simplex virus types 1 and 2 IgM were all found to be negative.

A deep shave biopsy obtained from the patient’s right knee revealed an atrophic interface dermatitis associated with a lymphocytic eccrine hidradenitis accompanied by abundant mesenchymal mucin deposition (Figure 4). Direct immunofluorescence (DIF) from the same area demonstrated IgG and IgM along the dermoepidermal junction with some granular deposition. Frozen sections performed on acral lesions demonstrated epidermal necrosis (Figure 5). Direct immunofluorescence of acral lesions was negative. In light of these findings, a diagnosis of Rowell syndrome (RS) was suspected to be the most likely explanation for the presentation.

Intravenous corticosteroids and antibiotics were administered, and over a 2-week hospitalization, the lesions on the feet and hands slowly reepithelialized. Physical therapy was required to aid in ambulation. The patient was discharged on a tapering course of oral prednisone and hydroxychloroquine. After 6 months of therapy with hydroxychloroquine 200 mg twice daily, the patient continued to experience recurrent bouts of acral lesions, and pulse doses of oral prednisone were required. The lesions currently are controlled with azathioprine 50 mg twice daily and prednisone 10 mg by mouth daily.

Comment

The 4 prototypical patients identified by Rowell et al¹ in 1963 in the first account of the eponymous syndrome were all females with discoid lupus erythematosus (DLE) and perniosis. In addition, they all displayed positive RF and saline extract of human tissue antibodies (analogous to anti-Ro/SS-A and anti-La/SS-B).² Since then, at least 132 patients with clinical symptoms suspicious of RS have been identified with variations on these original criteria.³ The reported permutations of the lupus component of the disease include cutaneous LE (CLE), bullous systemic LE, necrotic lesions associated with antiphospholipid syndrome, annular/polycyclic SCLE, systemic LE (SLE) without CLE, SLE with lupus nephritis, SLE with pericarditis, SLE with systemic vasculitis, Sjögren syndrome, rheumatoid arthritis, and necrotizing lymphadenitis.² In addition, variations of the erythema multiforme (EM)–like lesions found in reported cases include changes to their gross appearance (flat vs raised), location (acral or mucosal involvement), and resemblance to other conditions (Stevens-Johnson syndrome or toxic epidermal necrolysis).^2,3 From this information alone, it is clear that, as further cases have been chronicled, defining exact criteria for the disease has been challenging.

The essential question concerning the existence of RS hinges on the strength of its distinctiveness: Is it a unique disorder or merely another variant of lupus? Antiga et al² concluded that it should be characterized as a variant of SCLE. Lee at al⁴ agreed, stating that “[i]n view of the lack of specific features that distinguish RS from LE, Kuhn et al⁵ suggested that [RS] is probably not a distinct entity and is now widely considered to be a variant of SCLE.” One of the primary contributors to this conclusion is that the laboratory findings of reported patients with SCLE have more closely mirrored the original cases from Rowell et al’s¹ report than those of typical LE. Patients with SCLE have demonstrated positive ANA antibodies in 60% to 80% of cases, positive anti-Ro/SS-A antibodies in 40% to 100% of cases, positive anti-La/SS-B antibodies in 12% to 42% of cases, positive anti–double-stranded DNA in 1.2% to 10% of cases, and positive RF antibodies in 33% of cases.² An argument could certainly be made to ascribe our patient’s condition to an SCLE variant, as 4 of 5 preceding laboratory findings were found to be positive; however, the majority of reported cases of SCLE have been linked to drugs (ie, hydrochlorothiazide, angiotensin-converting enzyme inhibitors, calcium channel blockers, terbinafine),² which has not commonly been the attributable etiology of other cases of RS, including the 4 cases reported by Rowell et al.¹

In a review of the literature on RS since 2010 in addition to their report of 132 new cases, Torchia et al³ outlined a set of diagnostic standards for the condition consisting of major and minor criteria. According to the authors, if all 4 major and 1 minor criteria are met, the patient meets the standards for true RS. The major criteria include the following: (1) presence of chronic CLE [DLE and/or chilblain]; (2) presence of EM-like lesions [typical or atypical targets]; (3) at least 1 positivity among speckled ANA, anti-Ro/SS-A, and anti-La/SS-B antibodies; and (4) negative DIF on lesional EM-like targetoid lesions. The minor criteria include the following: (1) absence of infectious or pharmacologic triggers; (2) absence of typical EM location (acral and mucosal); and (3) presence of at least 1 additional American College of Rheumatology criterion for diagnosis of SLE⁸ besides discoid rash and positive ANA antibodies and excluding photosensitivity, malar rash, and oral ulcers. Using these criteria, the patient in our case met the standards for diagnosis of RS.

One area of disagreement that has been encountered in the literature is the exact histologic determination of true RS, specifically related to the microscopic findings of the EM-like lesions. Two cases presented by Modi et al⁶ were interpreted under the stipulation that true RS must contain histologic LE and histologic EM. Because the EM-appearing lesions revealed LE histology, the cases were concluded to be variants of LE. These cases are similar to our case in that the EM-like lesions in our patient demonstrated LE pathology. Torchia et al,³ as demonstrated in the above criteria, seemed to be less concerned about the histology of the EM-like lesions, only requiring them to show negative DIF.

Conclusion

In the search for answers concerning RS, many unanswered questions remain: Where should the line be drawn in the inclusion of so many variations of both the LE and EM components of the condition? Also, should these elements even be approached as distinct components in the first place? Viewing the majority of RS cases as simply simultaneous LE and EM, Shteyngarts et al⁷ concluded that “the concomitant occurrence of EM with LE did not change the course, therapy, or prognosis of either disease. SLE and DLE can coexist with EM, but the coexistence does not impart any unusual characteristic to either illness. Rowell’s syndrome is not reproducible, and the immunologic disturbances in such patients are probably coincidental.”

If the condition is a genuine pathological individuality, should we not view the seemingly separate LE and EM as the product of a single underlying biochemical process? These questions and others in the search for a true definition of the disease should continue to be debated. It is clear that further investigation is warranted in the understanding of the underlying mechanism of the pathology.

Case Report

A 37-year-old woman was admitted to the intensive care unit secondary to the acute development of an erythematous rash with tissue sloughing that involved acral sites and mucosal surfaces. Her medical history was notable for anti-Ro/Sjögren syndrome antigen A (SS-A)–positive lupus erythematosus (LE) with a morphologic semblance to subacute cutaneous LE (SCLE). Prior treatment had included oral corticosteroids. In addition, she reported a concurrent history of acral and mucosal lesions that appeared to flare with her lupus. The nature of these lesions was not clear to the patient or her physicians. Before this particular episode, her primary care physician had attempted to wean her off of the corticosteroids. As she dropped below 20 mg of prednisone daily, new lesions developed. The patient stated that her social situation was poor and that these lesions did seem to develop more frequently during times of physical and emotional stress. She recounted her first episode developing during her second pregnancy. Oral prednisone and over-the-counter calcium with vitamin D were her only reported medications. She denied the use of any other medications, including nonsteroidal anti-inflammatory drugs, acetaminophen, and recent antibiotic therapy.

Dermatology was called in for consultation, and physical examination revealed areas of epidermal sloughing on the hands and feet. Complete clinical exposure of the underlying dermis was noted with remarkable tenderness. These lesions were noted to be in various stages of healing (Figure 1). Figure 2 displays a lesion in early development. The mucosal surfaces of the lips and eyes demonstrated hemorrhagic crusting, and some tissue sloughing was noted on the ears. A widespread erythematous exanthema with fine scaling was noted on the face, neck, chest, back, abdomen, arms, and legs (Figure 3).

Laboratory evaluation revealed positive antinuclear antibodies (ANAs), anti-Ro/SS-A antibodies, anti-La/Sjögren syndrome antigen B (SS-B) antibodies, and anti–double-stranded DNA. The hemoglobin level was 9.4 g/dL (reference range, 12–15 g/dL) and hematocrit was 28.8% (reference range, 36%–47%). The mean corpuscular hemoglobin level was 32 pg/cell (reference range, 27–31 pg/cell), and the mean corpuscular hemoglobin concentration was 32.5 g/dL (reference range, 30–35 g/dL). Rheumatoid factor (RF) and herpes simplex virus types 1 and 2 IgM were all found to be negative.

A deep shave biopsy obtained from the patient’s right knee revealed an atrophic interface dermatitis associated with a lymphocytic eccrine hidradenitis accompanied by abundant mesenchymal mucin deposition (Figure 4). Direct immunofluorescence (DIF) from the same area demonstrated IgG and IgM along the dermoepidermal junction with some granular deposition. Frozen sections performed on acral lesions demonstrated epidermal necrosis (Figure 5). Direct immunofluorescence of acral lesions was negative. In light of these findings, a diagnosis of Rowell syndrome (RS) was suspected to be the most likely explanation for the presentation.

Intravenous corticosteroids and antibiotics were administered, and over a 2-week hospitalization, the lesions on the feet and hands slowly reepithelialized. Physical therapy was required to aid in ambulation. The patient was discharged on a tapering course of oral prednisone and hydroxychloroquine. After 6 months of therapy with hydroxychloroquine 200 mg twice daily, the patient continued to experience recurrent bouts of acral lesions, and pulse doses of oral prednisone were required. The lesions currently are controlled with azathioprine 50 mg twice daily and prednisone 10 mg by mouth daily.

Comment

The 4 prototypical patients identified by Rowell et al¹ in 1963 in the first account of the eponymous syndrome were all females with discoid lupus erythematosus (DLE) and perniosis. In addition, they all displayed positive RF and saline extract of human tissue antibodies (analogous to anti-Ro/SS-A and anti-La/SS-B).² Since then, at least 132 patients with clinical symptoms suspicious of RS have been identified with variations on these original criteria.³ The reported permutations of the lupus component of the disease include cutaneous LE (CLE), bullous systemic LE, necrotic lesions associated with antiphospholipid syndrome, annular/polycyclic SCLE, systemic LE (SLE) without CLE, SLE with lupus nephritis, SLE with pericarditis, SLE with systemic vasculitis, Sjögren syndrome, rheumatoid arthritis, and necrotizing lymphadenitis.² In addition, variations of the erythema multiforme (EM)–like lesions found in reported cases include changes to their gross appearance (flat vs raised), location (acral or mucosal involvement), and resemblance to other conditions (Stevens-Johnson syndrome or toxic epidermal necrolysis).^2,3 From this information alone, it is clear that, as further cases have been chronicled, defining exact criteria for the disease has been challenging.

The essential question concerning the existence of RS hinges on the strength of its distinctiveness: Is it a unique disorder or merely another variant of lupus? Antiga et al² concluded that it should be characterized as a variant of SCLE. Lee at al⁴ agreed, stating that “[i]n view of the lack of specific features that distinguish RS from LE, Kuhn et al⁵ suggested that [RS] is probably not a distinct entity and is now widely considered to be a variant of SCLE.” One of the primary contributors to this conclusion is that the laboratory findings of reported patients with SCLE have more closely mirrored the original cases from Rowell et al’s¹ report than those of typical LE. Patients with SCLE have demonstrated positive ANA antibodies in 60% to 80% of cases, positive anti-Ro/SS-A antibodies in 40% to 100% of cases, positive anti-La/SS-B antibodies in 12% to 42% of cases, positive anti–double-stranded DNA in 1.2% to 10% of cases, and positive RF antibodies in 33% of cases.² An argument could certainly be made to ascribe our patient’s condition to an SCLE variant, as 4 of 5 preceding laboratory findings were found to be positive; however, the majority of reported cases of SCLE have been linked to drugs (ie, hydrochlorothiazide, angiotensin-converting enzyme inhibitors, calcium channel blockers, terbinafine),² which has not commonly been the attributable etiology of other cases of RS, including the 4 cases reported by Rowell et al.¹

In a review of the literature on RS since 2010 in addition to their report of 132 new cases, Torchia et al³ outlined a set of diagnostic standards for the condition consisting of major and minor criteria. According to the authors, if all 4 major and 1 minor criteria are met, the patient meets the standards for true RS. The major criteria include the following: (1) presence of chronic CLE [DLE and/or chilblain]; (2) presence of EM-like lesions [typical or atypical targets]; (3) at least 1 positivity among speckled ANA, anti-Ro/SS-A, and anti-La/SS-B antibodies; and (4) negative DIF on lesional EM-like targetoid lesions. The minor criteria include the following: (1) absence of infectious or pharmacologic triggers; (2) absence of typical EM location (acral and mucosal); and (3) presence of at least 1 additional American College of Rheumatology criterion for diagnosis of SLE⁸ besides discoid rash and positive ANA antibodies and excluding photosensitivity, malar rash, and oral ulcers. Using these criteria, the patient in our case met the standards for diagnosis of RS.

One area of disagreement that has been encountered in the literature is the exact histologic determination of true RS, specifically related to the microscopic findings of the EM-like lesions. Two cases presented by Modi et al⁶ were interpreted under the stipulation that true RS must contain histologic LE and histologic EM. Because the EM-appearing lesions revealed LE histology, the cases were concluded to be variants of LE. These cases are similar to our case in that the EM-like lesions in our patient demonstrated LE pathology. Torchia et al,³ as demonstrated in the above criteria, seemed to be less concerned about the histology of the EM-like lesions, only requiring them to show negative DIF.

Conclusion

In the search for answers concerning RS, many unanswered questions remain: Where should the line be drawn in the inclusion of so many variations of both the LE and EM components of the condition? Also, should these elements even be approached as distinct components in the first place? Viewing the majority of RS cases as simply simultaneous LE and EM, Shteyngarts et al⁷ concluded that “the concomitant occurrence of EM with LE did not change the course, therapy, or prognosis of either disease. SLE and DLE can coexist with EM, but the coexistence does not impart any unusual characteristic to either illness. Rowell’s syndrome is not reproducible, and the immunologic disturbances in such patients are probably coincidental.”

If the condition is a genuine pathological individuality, should we not view the seemingly separate LE and EM as the product of a single underlying biochemical process? These questions and others in the search for a true definition of the disease should continue to be debated. It is clear that further investigation is warranted in the understanding of the underlying mechanism of the pathology.

The Diagnosis: Lymphomatoid Papulosis

A shave biopsy of an established lesion on the volar aspect of the left wrist was performed (Figure 1). The biopsy showed an ulcerated nodular lesion characterized by a dense mixed inflammatory cell infiltrate in the dermis composed of lymphocytes, histiocytes, scattered neutrophils, and numerous eosinophils (Figure 2). Notably there was a minor population of large atypical cells with immunoblastic and anaplastic morphology present individually and in small clusters most prominently within the upper dermis (Figures 3 and 4). Immunohistochemistry of the anaplastic cells revealed a CD30⁺, CD3⁻, CD4⁺, CD5⁻, CD8⁻, CD2⁻, CD7⁻, CD56⁻, ALK1⁻ (anaplastic lymphoma kinase-1), PAX5⁻ (paired box protein-5), CD20⁻, and CD15⁻ phenotype. These morphologic and immunohistochemical features suggested a CD30⁺ cutaneous lymphoproliferative disorder. The clinical history of recurrent self-healing papulonodules in an otherwise-healthy patient established the diagnosis of lymphomatoid papulosis (LyP).

Lymphomatoid papulosis is a lymphoproliferative disorder characterized by recurrent crops of self-resolving eruptive papulonodular skin lesions that may show a variety of histologic features including a CD30⁺ malignant T-cell lymphoma.¹ Lymphomatoid papulosis was first described in 1968¹ but debate continues whether the condition should be considered malignant or benign.² Although the prognosis is excellent, LyP is characterized by a protracted course, often lasting many years. Additionally, these patients have a lifelong increased risk for development of a second cutaneous or systemic lymphoma such as mycosis fungoides (MF), cutaneous or nodal anaplastic large cell lymphoma (ALCL), or Hodgkin lymphoma, among others.

Lymphomatoid papulosis is a rare disease occurring in all ethnic groups and at any age, though most commonly presenting in the fifth decade of life. Finding large atypical T cells expressing CD30 in recurring skin lesions is highly suggestive of LyP; however, large CD30⁺ cells also can be seen in numerous benign reactive processes such as arthropod assault, drug eruption, viral skin infections, and other dermatoses, thus clinical correlation is always paramount. The cause of LyP is largely unknown; however, spontaneous regression may be explained by CD30-CD30 ligand interaction³ as well as an increased proapoptotic milieu.⁴ Specific translocations such as interferon regulatory factor-4 have been hypothesized as a risk factor for malignant progression.^5-7 Additionally, an inactivating gene mutation resulting in loss of transforming growth factor β1 receptor expression and subsequent unresponsiveness to the growth inhibitory effect of transforming growth factor β may play a role in progression of LyP to ALCL.⁸

Clinically, LyP consists of red-brown papules and nodules generally smaller than 2 cm, often with central hemorrhage, necrosis, and crusting. Lesions are at different stages of eruption and resolution. They are often grouped but may be disseminated. Spontaneous regression typically occurs within 3 to 8 weeks. Pruritus or mild tenderness may occur as well as residual hyperpigmentation or scarring. Systemic symptoms are notably absent.

The histologic features of LyP vary according to the age of the lesion and subtype.² Early lesions may only show a few inflammatory cells, but as lesions evolve, larger immunoblastlike CD30⁺ atypical cells accumulate that may resemble the Reed-Sternberg cells of Hodgkin lymphoma. Of the 5 subtypes, the most common is type A. It is characterized by a wedge-shaped infiltrate with a mixed population of scattered or clustered, large, atypical CD30⁺ cells, lymphocytes, neutrophils, eosinophils, and histiocytes.⁹ Frequent mitoses often are seen. Type B appears similar to MF due to a predominantly epidermotropic infiltrate of CD3⁺ and often CD30⁻ atypical cells. Spontaneously regressing papules favor LyP, whereas persistent patches or plaques favor MF. Type C appears identical to ALCL with diffuse sheets of large atypical CD30⁺ cells and relatively few inflammatory cells, but spontaneously regressing lesions again favor LyP, whereas persistent tumors favor ALCL. Type D appears similar to primary cutaneous aggressive epidermotropic CD8⁺ cytotoxic T cell lymphoma due to a markedly epidermotropic infiltrate of small atypical CD8⁺ and CD30⁺ lymphocytes, often TIA-1⁺ (T-cell intracytoplasmic antigen-1) or granzyme B⁺, but CD30 positivity and self-resolving lesions favor LyP. Type E mimics extranodal natural killer/T cell lymphoma (nasal type) due to angioinvasive CD30⁺ and beta F1⁺ T lymphocytes, often CD8⁺ and/or TIA-1⁺, but self-resolving lesions again favor LyP, as well as absence of Epstein-Barr virus and CD56⁻.⁹

The most common therapeutic approaches to LyP include topical steroids, phototherapy, and low-dose methotrexate.¹⁰ However, treatment does not change overall disease course or reduce the future risk for developing an associated lymphoma. Accordingly, abstaining from active therapeutic intervention is reasonable, especially in patients with only a few asymptomatic lesions.

The Diagnosis: Lymphomatoid Papulosis

A shave biopsy of an established lesion on the volar aspect of the left wrist was performed (Figure 1). The biopsy showed an ulcerated nodular lesion characterized by a dense mixed inflammatory cell infiltrate in the dermis composed of lymphocytes, histiocytes, scattered neutrophils, and numerous eosinophils (Figure 2). Notably there was a minor population of large atypical cells with immunoblastic and anaplastic morphology present individually and in small clusters most prominently within the upper dermis (Figures 3 and 4). Immunohistochemistry of the anaplastic cells revealed a CD30⁺, CD3⁻, CD4⁺, CD5⁻, CD8⁻, CD2⁻, CD7⁻, CD56⁻, ALK1⁻ (anaplastic lymphoma kinase-1), PAX5⁻ (paired box protein-5), CD20⁻, and CD15⁻ phenotype. These morphologic and immunohistochemical features suggested a CD30⁺ cutaneous lymphoproliferative disorder. The clinical history of recurrent self-healing papulonodules in an otherwise-healthy patient established the diagnosis of lymphomatoid papulosis (LyP).

Lymphomatoid papulosis is a lymphoproliferative disorder characterized by recurrent crops of self-resolving eruptive papulonodular skin lesions that may show a variety of histologic features including a CD30⁺ malignant T-cell lymphoma.¹ Lymphomatoid papulosis was first described in 1968¹ but debate continues whether the condition should be considered malignant or benign.² Although the prognosis is excellent, LyP is characterized by a protracted course, often lasting many years. Additionally, these patients have a lifelong increased risk for development of a second cutaneous or systemic lymphoma such as mycosis fungoides (MF), cutaneous or nodal anaplastic large cell lymphoma (ALCL), or Hodgkin lymphoma, among others.

Lymphomatoid papulosis is a rare disease occurring in all ethnic groups and at any age, though most commonly presenting in the fifth decade of life. Finding large atypical T cells expressing CD30 in recurring skin lesions is highly suggestive of LyP; however, large CD30⁺ cells also can be seen in numerous benign reactive processes such as arthropod assault, drug eruption, viral skin infections, and other dermatoses, thus clinical correlation is always paramount. The cause of LyP is largely unknown; however, spontaneous regression may be explained by CD30-CD30 ligand interaction³ as well as an increased proapoptotic milieu.⁴ Specific translocations such as interferon regulatory factor-4 have been hypothesized as a risk factor for malignant progression.^5-7 Additionally, an inactivating gene mutation resulting in loss of transforming growth factor β1 receptor expression and subsequent unresponsiveness to the growth inhibitory effect of transforming growth factor β may play a role in progression of LyP to ALCL.⁸

Clinically, LyP consists of red-brown papules and nodules generally smaller than 2 cm, often with central hemorrhage, necrosis, and crusting. Lesions are at different stages of eruption and resolution. They are often grouped but may be disseminated. Spontaneous regression typically occurs within 3 to 8 weeks. Pruritus or mild tenderness may occur as well as residual hyperpigmentation or scarring. Systemic symptoms are notably absent.

The histologic features of LyP vary according to the age of the lesion and subtype.² Early lesions may only show a few inflammatory cells, but as lesions evolve, larger immunoblastlike CD30⁺ atypical cells accumulate that may resemble the Reed-Sternberg cells of Hodgkin lymphoma. Of the 5 subtypes, the most common is type A. It is characterized by a wedge-shaped infiltrate with a mixed population of scattered or clustered, large, atypical CD30⁺ cells, lymphocytes, neutrophils, eosinophils, and histiocytes.⁹ Frequent mitoses often are seen. Type B appears similar to MF due to a predominantly epidermotropic infiltrate of CD3⁺ and often CD30⁻ atypical cells. Spontaneously regressing papules favor LyP, whereas persistent patches or plaques favor MF. Type C appears identical to ALCL with diffuse sheets of large atypical CD30⁺ cells and relatively few inflammatory cells, but spontaneously regressing lesions again favor LyP, whereas persistent tumors favor ALCL. Type D appears similar to primary cutaneous aggressive epidermotropic CD8⁺ cytotoxic T cell lymphoma due to a markedly epidermotropic infiltrate of small atypical CD8⁺ and CD30⁺ lymphocytes, often TIA-1⁺ (T-cell intracytoplasmic antigen-1) or granzyme B⁺, but CD30 positivity and self-resolving lesions favor LyP. Type E mimics extranodal natural killer/T cell lymphoma (nasal type) due to angioinvasive CD30⁺ and beta F1⁺ T lymphocytes, often CD8⁺ and/or TIA-1⁺, but self-resolving lesions again favor LyP, as well as absence of Epstein-Barr virus and CD56⁻.⁹

The most common therapeutic approaches to LyP include topical steroids, phototherapy, and low-dose methotrexate.¹⁰ However, treatment does not change overall disease course or reduce the future risk for developing an associated lymphoma. Accordingly, abstaining from active therapeutic intervention is reasonable, especially in patients with only a few asymptomatic lesions.

The Diagnosis: Lymphomatoid Papulosis

A shave biopsy of an established lesion on the volar aspect of the left wrist was performed (Figure 1). The biopsy showed an ulcerated nodular lesion characterized by a dense mixed inflammatory cell infiltrate in the dermis composed of lymphocytes, histiocytes, scattered neutrophils, and numerous eosinophils (Figure 2). Notably there was a minor population of large atypical cells with immunoblastic and anaplastic morphology present individually and in small clusters most prominently within the upper dermis (Figures 3 and 4). Immunohistochemistry of the anaplastic cells revealed a CD30⁺, CD3⁻, CD4⁺, CD5⁻, CD8⁻, CD2⁻, CD7⁻, CD56⁻, ALK1⁻ (anaplastic lymphoma kinase-1), PAX5⁻ (paired box protein-5), CD20⁻, and CD15⁻ phenotype. These morphologic and immunohistochemical features suggested a CD30⁺ cutaneous lymphoproliferative disorder. The clinical history of recurrent self-healing papulonodules in an otherwise-healthy patient established the diagnosis of lymphomatoid papulosis (LyP).

Lymphomatoid papulosis is a lymphoproliferative disorder characterized by recurrent crops of self-resolving eruptive papulonodular skin lesions that may show a variety of histologic features including a CD30⁺ malignant T-cell lymphoma.¹ Lymphomatoid papulosis was first described in 1968¹ but debate continues whether the condition should be considered malignant or benign.² Although the prognosis is excellent, LyP is characterized by a protracted course, often lasting many years. Additionally, these patients have a lifelong increased risk for development of a second cutaneous or systemic lymphoma such as mycosis fungoides (MF), cutaneous or nodal anaplastic large cell lymphoma (ALCL), or Hodgkin lymphoma, among others.

Lymphomatoid papulosis is a rare disease occurring in all ethnic groups and at any age, though most commonly presenting in the fifth decade of life. Finding large atypical T cells expressing CD30 in recurring skin lesions is highly suggestive of LyP; however, large CD30⁺ cells also can be seen in numerous benign reactive processes such as arthropod assault, drug eruption, viral skin infections, and other dermatoses, thus clinical correlation is always paramount. The cause of LyP is largely unknown; however, spontaneous regression may be explained by CD30-CD30 ligand interaction³ as well as an increased proapoptotic milieu.⁴ Specific translocations such as interferon regulatory factor-4 have been hypothesized as a risk factor for malignant progression.^5-7 Additionally, an inactivating gene mutation resulting in loss of transforming growth factor β1 receptor expression and subsequent unresponsiveness to the growth inhibitory effect of transforming growth factor β may play a role in progression of LyP to ALCL.⁸

Clinically, LyP consists of red-brown papules and nodules generally smaller than 2 cm, often with central hemorrhage, necrosis, and crusting. Lesions are at different stages of eruption and resolution. They are often grouped but may be disseminated. Spontaneous regression typically occurs within 3 to 8 weeks. Pruritus or mild tenderness may occur as well as residual hyperpigmentation or scarring. Systemic symptoms are notably absent.

The histologic features of LyP vary according to the age of the lesion and subtype.² Early lesions may only show a few inflammatory cells, but as lesions evolve, larger immunoblastlike CD30⁺ atypical cells accumulate that may resemble the Reed-Sternberg cells of Hodgkin lymphoma. Of the 5 subtypes, the most common is type A. It is characterized by a wedge-shaped infiltrate with a mixed population of scattered or clustered, large, atypical CD30⁺ cells, lymphocytes, neutrophils, eosinophils, and histiocytes.⁹ Frequent mitoses often are seen. Type B appears similar to MF due to a predominantly epidermotropic infiltrate of CD3⁺ and often CD30⁻ atypical cells. Spontaneously regressing papules favor LyP, whereas persistent patches or plaques favor MF. Type C appears identical to ALCL with diffuse sheets of large atypical CD30⁺ cells and relatively few inflammatory cells, but spontaneously regressing lesions again favor LyP, whereas persistent tumors favor ALCL. Type D appears similar to primary cutaneous aggressive epidermotropic CD8⁺ cytotoxic T cell lymphoma due to a markedly epidermotropic infiltrate of small atypical CD8⁺ and CD30⁺ lymphocytes, often TIA-1⁺ (T-cell intracytoplasmic antigen-1) or granzyme B⁺, but CD30 positivity and self-resolving lesions favor LyP. Type E mimics extranodal natural killer/T cell lymphoma (nasal type) due to angioinvasive CD30⁺ and beta F1⁺ T lymphocytes, often CD8⁺ and/or TIA-1⁺, but self-resolving lesions again favor LyP, as well as absence of Epstein-Barr virus and CD56⁻.⁹

The most common therapeutic approaches to LyP include topical steroids, phototherapy, and low-dose methotrexate.¹⁰ However, treatment does not change overall disease course or reduce the future risk for developing an associated lymphoma. Accordingly, abstaining from active therapeutic intervention is reasonable, especially in patients with only a few asymptomatic lesions.

A genetic predisposition to higher serum calcium levels was significantly linked with coronary artery disease and myocardial infarction in a large mendelian randomization study published online July 25 in JAMA.

Each 0.5-mg rise in genetically predicted serum calcium concentration increased the odds of coronary artery disease (CAD) and myocardial infarction by about 25%, reported Susanna C. Larsson, Ph.D., of Karolinska Institutet in Stockholm, Sweden, and her associates. It remains unclear whether short- or medium-term calcium supplementation also increases the risk of these outcomes, they added.

Observational studies have linked high serum calcium with cardiovascular disease, but such studies are subject to confounding, the researchers noted. Randomized trials indicate that calcium supplementation might contribute to MI, but the trials are not designed to quantify long-term risks. Therefore, the investigators evaluated a proxy for lifelong hypercalcemia – six single nucleotide polymorphisms (SNPs) that have been linked to high serum calcium, but not to other CAD risk factors such as type 2 diabetes, fasting glucose and insulin levels, body mass index, waist-to-hip ratio, major lipids, or hypertension (JAMA. 2017 Jul 25;318[4]:371-80. doi: 10.1001/jama.2017.8981).

To examine how these SNPs affect the risk of CAD and MI, the researchers analyzed summary statistics for 184,305 individuals from a meta-analysis of CAD genome-wide association studies (Nat Genet. 2015;47:1121-30), including 60,801 cases (of whom about 70% also had MI) and 123,504 controls.

Together, these six SNPs explained about 0.8% of variations in serum calcium levels. Each 0.5-mg/dL (about one standard deviation) increase in genetically predicted serum calcium level significantly increased the risk of CAD (odds ratio, 1.25; 95% confidence interval, 1.08-1.45; P = .003) and MI (OR, 1.24; 95% CI, 1.05-1.46; P = .009). The genetic variant rs1801725 exerted the greatest effect on serum calcium levels, the investigators noted. This SNP affects the CASR gene, which encodes a calcium-sensing receptor that “plays a key role in calcium homeostasis.” However, four of the other five variants also had odds ratios above 1.0, and three had odds ratios above 1.25. A sensitivity analysis that excluded the CASR variant generated an identical odds ratio, although the confidence interval was wider. Studies of other risk factors for CAD have yielded odds ratios between 1.3 (triglyceride levels) and 1.7 (LDL cholesterol levels), the researchers noted.

A link between calcium supplementation and MI remains debatable. However, supplementation can lead to hypercalcemia and greater formation of insoluble calciprotein particles, the investigators said. Coronary artery disease might result from downstream effects on vascular calcification, vascular cells, blood coagulation pathways, or gene expression, but such mechanisms need more study, they added.

This analysis included men and women from the United States, Canada, the United Kingdom, Germany, Sweden, Ireland, the Netherlands, Finland, Iceland, Italy, Estonia, Lebanon, China, Korea, India, Pakistan and Greece. Participants tended to be men in their 50s and 60s, but more than half of studies lacked data on age and sex. Nearly all participants were of white European ancestry.

Karolinska Institutet supported Dr. Larsson. The investigators reported having no relevant conflicts of interest.

[email protected]

A genetic predisposition to higher serum calcium levels was significantly linked with coronary artery disease and myocardial infarction in a large mendelian randomization study published online July 25 in JAMA.

Each 0.5-mg rise in genetically predicted serum calcium concentration increased the odds of coronary artery disease (CAD) and myocardial infarction by about 25%, reported Susanna C. Larsson, Ph.D., of Karolinska Institutet in Stockholm, Sweden, and her associates. It remains unclear whether short- or medium-term calcium supplementation also increases the risk of these outcomes, they added.

Observational studies have linked high serum calcium with cardiovascular disease, but such studies are subject to confounding, the researchers noted. Randomized trials indicate that calcium supplementation might contribute to MI, but the trials are not designed to quantify long-term risks. Therefore, the investigators evaluated a proxy for lifelong hypercalcemia – six single nucleotide polymorphisms (SNPs) that have been linked to high serum calcium, but not to other CAD risk factors such as type 2 diabetes, fasting glucose and insulin levels, body mass index, waist-to-hip ratio, major lipids, or hypertension (JAMA. 2017 Jul 25;318[4]:371-80. doi: 10.1001/jama.2017.8981).

To examine how these SNPs affect the risk of CAD and MI, the researchers analyzed summary statistics for 184,305 individuals from a meta-analysis of CAD genome-wide association studies (Nat Genet. 2015;47:1121-30), including 60,801 cases (of whom about 70% also had MI) and 123,504 controls.

Together, these six SNPs explained about 0.8% of variations in serum calcium levels. Each 0.5-mg/dL (about one standard deviation) increase in genetically predicted serum calcium level significantly increased the risk of CAD (odds ratio, 1.25; 95% confidence interval, 1.08-1.45; P = .003) and MI (OR, 1.24; 95% CI, 1.05-1.46; P = .009). The genetic variant rs1801725 exerted the greatest effect on serum calcium levels, the investigators noted. This SNP affects the CASR gene, which encodes a calcium-sensing receptor that “plays a key role in calcium homeostasis.” However, four of the other five variants also had odds ratios above 1.0, and three had odds ratios above 1.25. A sensitivity analysis that excluded the CASR variant generated an identical odds ratio, although the confidence interval was wider. Studies of other risk factors for CAD have yielded odds ratios between 1.3 (triglyceride levels) and 1.7 (LDL cholesterol levels), the researchers noted.

A link between calcium supplementation and MI remains debatable. However, supplementation can lead to hypercalcemia and greater formation of insoluble calciprotein particles, the investigators said. Coronary artery disease might result from downstream effects on vascular calcification, vascular cells, blood coagulation pathways, or gene expression, but such mechanisms need more study, they added.

This analysis included men and women from the United States, Canada, the United Kingdom, Germany, Sweden, Ireland, the Netherlands, Finland, Iceland, Italy, Estonia, Lebanon, China, Korea, India, Pakistan and Greece. Participants tended to be men in their 50s and 60s, but more than half of studies lacked data on age and sex. Nearly all participants were of white European ancestry.

Karolinska Institutet supported Dr. Larsson. The investigators reported having no relevant conflicts of interest.

[email protected]

A genetic predisposition to higher serum calcium levels was significantly linked with coronary artery disease and myocardial infarction in a large mendelian randomization study published online July 25 in JAMA.

Each 0.5-mg rise in genetically predicted serum calcium concentration increased the odds of coronary artery disease (CAD) and myocardial infarction by about 25%, reported Susanna C. Larsson, Ph.D., of Karolinska Institutet in Stockholm, Sweden, and her associates. It remains unclear whether short- or medium-term calcium supplementation also increases the risk of these outcomes, they added.

Observational studies have linked high serum calcium with cardiovascular disease, but such studies are subject to confounding, the researchers noted. Randomized trials indicate that calcium supplementation might contribute to MI, but the trials are not designed to quantify long-term risks. Therefore, the investigators evaluated a proxy for lifelong hypercalcemia – six single nucleotide polymorphisms (SNPs) that have been linked to high serum calcium, but not to other CAD risk factors such as type 2 diabetes, fasting glucose and insulin levels, body mass index, waist-to-hip ratio, major lipids, or hypertension (JAMA. 2017 Jul 25;318[4]:371-80. doi: 10.1001/jama.2017.8981).

To examine how these SNPs affect the risk of CAD and MI, the researchers analyzed summary statistics for 184,305 individuals from a meta-analysis of CAD genome-wide association studies (Nat Genet. 2015;47:1121-30), including 60,801 cases (of whom about 70% also had MI) and 123,504 controls.

Together, these six SNPs explained about 0.8% of variations in serum calcium levels. Each 0.5-mg/dL (about one standard deviation) increase in genetically predicted serum calcium level significantly increased the risk of CAD (odds ratio, 1.25; 95% confidence interval, 1.08-1.45; P = .003) and MI (OR, 1.24; 95% CI, 1.05-1.46; P = .009). The genetic variant rs1801725 exerted the greatest effect on serum calcium levels, the investigators noted. This SNP affects the CASR gene, which encodes a calcium-sensing receptor that “plays a key role in calcium homeostasis.” However, four of the other five variants also had odds ratios above 1.0, and three had odds ratios above 1.25. A sensitivity analysis that excluded the CASR variant generated an identical odds ratio, although the confidence interval was wider. Studies of other risk factors for CAD have yielded odds ratios between 1.3 (triglyceride levels) and 1.7 (LDL cholesterol levels), the researchers noted.

A link between calcium supplementation and MI remains debatable. However, supplementation can lead to hypercalcemia and greater formation of insoluble calciprotein particles, the investigators said. Coronary artery disease might result from downstream effects on vascular calcification, vascular cells, blood coagulation pathways, or gene expression, but such mechanisms need more study, they added.

This analysis included men and women from the United States, Canada, the United Kingdom, Germany, Sweden, Ireland, the Netherlands, Finland, Iceland, Italy, Estonia, Lebanon, China, Korea, India, Pakistan and Greece. Participants tended to be men in their 50s and 60s, but more than half of studies lacked data on age and sex. Nearly all participants were of white European ancestry.

Karolinska Institutet supported Dr. Larsson. The investigators reported having no relevant conflicts of interest.

[email protected]