Article

The Diagnosis: Cutaneous Leishmaniasis

A punch biopsy of the skin showed pseudoepitheliomatous hyperplasia of the epidermis with dermal granulomatous and suppurative inflammation; tissue cultures remained sterile. Polymerase chain reaction testing of the skin revealed the presence of Leishmania guyanensis complex. Leishmaniasis is a widespread parasitic disease transmitted via sandflies that often is seen in children and young adults.¹ Although leishmaniasis is endemic to several countries within Southeast Asia, East Africa, and Latin America, an increase in international travel has brought the disease to nonendemic regions. Therefore, it is crucial to obtain a detailed history of travel and exposure to sandflies in patients who have recently returned from endemic regions.

Leishmaniasis may present in 3 forms: cutaneous, mucocutaneous, or visceral. Cutaneous clinical findings vary depending on disease stage, causative species, and host immune activation. Presentation following a sandfly bite typically includes a papule that progresses to an erythematous nodule. Cutaneous leishmaniasis commonly occurs in areas of the body that are easily accessible to sandflies, such as the face, neck, and limbs. Mucocutaneous leishmaniasis presents with nasal or oral involvement several years after the onset of cutaneous leishmaniasis; however, it can coexist with cutaneous involvement. Without treatment, mucocutaneous leishmaniasis may lead to perforation of the nasal septum, destruction of the mouth, and life-threatening airway obstruction.¹ Determining the specific species is important due to the variation in treatment options and prognosis. Because Leishmania organisms are fastidious, obtaining a positive culture often is challenging. Polymerase chain reaction can be utilized for identification, with detection rates of 97%.¹ Systemic treatment is indicated for patients with multiple or large lesions; lesions on the hands, feet, face, or joints; or immunocompromised patients. Antimonial drugs are the first-line treatment for most forms of leishmaniasis, though increasing resistance has led to a decrease in efficacy.¹ Our patient ultimately was treated with 4 weeks of miltefosine 50 mg 3 times daily. She obtained full resolution of the lesions with no further treatment indicated.

Pemphigus vegetans may present with various clinical manifestations that often can lead to a delay in diagnosis. The Hallopeau subtype typically presents as pustular lesions, while the Neumann subtype may present as large vesiculobullous erosive lesions that rupture and form verrucous, crusted, vegetative plaques. The groin, inguinal folds, axillae, thighs, and flexural areas commonly are affected, but reports of nasal, vaginal, and conjunctival involvement also exist.²

Granuloma inguinale is a sexually transmitted ulcerative disease that is caused by infection with Klebsiella granulomatis. It typically is found in tropical and subtropical climates, including Australia, Brazil, India, and South Africa. The initial presentation includes a single papule or multiple papules or nodules in the genital area that progress to a painless ulcer. It can be diagnosed via biopsies or tissue smears, which will demonstrate the presence of inclusion bodies known as Donovan bodies.³

Cutaneous tuberculosis (TB) can have variable clinical presentations and may be acquired exogenously or endogenously. Cutaneous TB can be divided into 2 categories: exogenous TB caused by inoculation and endogenous TB due to direct spread or autoinoculation. Exogenous TB subtypes include tuberculous chancre and TB verrucosa cutis, while endogenous TB includes scrofuloderma, orificial TB, and lupus vulgaris.⁴ Patches and plaques are found in patients with lupus vulgaris and TB verrucosa cutis. Scrofuloderma, tuberculous chancre, and orificial TB can present as ulcerative or erosive lesions. Cutaneous TB infection can be diagnosed through a smear, culture, or polymerase chain reaction.⁴

Deep cutaneous fungal infections most commonly present in immunocompromised individuals, particularly those who are severely neutropenic and are receiving broad-spectrum systemic antimicrobial agents. Deep cutaneous fungal infections initially present as a papule and evolve into a pustule followed by a necrotic ulcer. The lesions typically are accompanied by a fever and/or vital sign abnormalities.⁵

The Diagnosis: Cutaneous Leishmaniasis

A punch biopsy of the skin showed pseudoepitheliomatous hyperplasia of the epidermis with dermal granulomatous and suppurative inflammation; tissue cultures remained sterile. Polymerase chain reaction testing of the skin revealed the presence of Leishmania guyanensis complex. Leishmaniasis is a widespread parasitic disease transmitted via sandflies that often is seen in children and young adults.¹ Although leishmaniasis is endemic to several countries within Southeast Asia, East Africa, and Latin America, an increase in international travel has brought the disease to nonendemic regions. Therefore, it is crucial to obtain a detailed history of travel and exposure to sandflies in patients who have recently returned from endemic regions.

Leishmaniasis may present in 3 forms: cutaneous, mucocutaneous, or visceral. Cutaneous clinical findings vary depending on disease stage, causative species, and host immune activation. Presentation following a sandfly bite typically includes a papule that progresses to an erythematous nodule. Cutaneous leishmaniasis commonly occurs in areas of the body that are easily accessible to sandflies, such as the face, neck, and limbs. Mucocutaneous leishmaniasis presents with nasal or oral involvement several years after the onset of cutaneous leishmaniasis; however, it can coexist with cutaneous involvement. Without treatment, mucocutaneous leishmaniasis may lead to perforation of the nasal septum, destruction of the mouth, and life-threatening airway obstruction.¹ Determining the specific species is important due to the variation in treatment options and prognosis. Because Leishmania organisms are fastidious, obtaining a positive culture often is challenging. Polymerase chain reaction can be utilized for identification, with detection rates of 97%.¹ Systemic treatment is indicated for patients with multiple or large lesions; lesions on the hands, feet, face, or joints; or immunocompromised patients. Antimonial drugs are the first-line treatment for most forms of leishmaniasis, though increasing resistance has led to a decrease in efficacy.¹ Our patient ultimately was treated with 4 weeks of miltefosine 50 mg 3 times daily. She obtained full resolution of the lesions with no further treatment indicated.

Pemphigus vegetans may present with various clinical manifestations that often can lead to a delay in diagnosis. The Hallopeau subtype typically presents as pustular lesions, while the Neumann subtype may present as large vesiculobullous erosive lesions that rupture and form verrucous, crusted, vegetative plaques. The groin, inguinal folds, axillae, thighs, and flexural areas commonly are affected, but reports of nasal, vaginal, and conjunctival involvement also exist.²

Granuloma inguinale is a sexually transmitted ulcerative disease that is caused by infection with Klebsiella granulomatis. It typically is found in tropical and subtropical climates, including Australia, Brazil, India, and South Africa. The initial presentation includes a single papule or multiple papules or nodules in the genital area that progress to a painless ulcer. It can be diagnosed via biopsies or tissue smears, which will demonstrate the presence of inclusion bodies known as Donovan bodies.³

Cutaneous tuberculosis (TB) can have variable clinical presentations and may be acquired exogenously or endogenously. Cutaneous TB can be divided into 2 categories: exogenous TB caused by inoculation and endogenous TB due to direct spread or autoinoculation. Exogenous TB subtypes include tuberculous chancre and TB verrucosa cutis, while endogenous TB includes scrofuloderma, orificial TB, and lupus vulgaris.⁴ Patches and plaques are found in patients with lupus vulgaris and TB verrucosa cutis. Scrofuloderma, tuberculous chancre, and orificial TB can present as ulcerative or erosive lesions. Cutaneous TB infection can be diagnosed through a smear, culture, or polymerase chain reaction.⁴

Deep cutaneous fungal infections most commonly present in immunocompromised individuals, particularly those who are severely neutropenic and are receiving broad-spectrum systemic antimicrobial agents. Deep cutaneous fungal infections initially present as a papule and evolve into a pustule followed by a necrotic ulcer. The lesions typically are accompanied by a fever and/or vital sign abnormalities.⁵

The Diagnosis: Cutaneous Leishmaniasis

A punch biopsy of the skin showed pseudoepitheliomatous hyperplasia of the epidermis with dermal granulomatous and suppurative inflammation; tissue cultures remained sterile. Polymerase chain reaction testing of the skin revealed the presence of Leishmania guyanensis complex. Leishmaniasis is a widespread parasitic disease transmitted via sandflies that often is seen in children and young adults.¹ Although leishmaniasis is endemic to several countries within Southeast Asia, East Africa, and Latin America, an increase in international travel has brought the disease to nonendemic regions. Therefore, it is crucial to obtain a detailed history of travel and exposure to sandflies in patients who have recently returned from endemic regions.

Leishmaniasis may present in 3 forms: cutaneous, mucocutaneous, or visceral. Cutaneous clinical findings vary depending on disease stage, causative species, and host immune activation. Presentation following a sandfly bite typically includes a papule that progresses to an erythematous nodule. Cutaneous leishmaniasis commonly occurs in areas of the body that are easily accessible to sandflies, such as the face, neck, and limbs. Mucocutaneous leishmaniasis presents with nasal or oral involvement several years after the onset of cutaneous leishmaniasis; however, it can coexist with cutaneous involvement. Without treatment, mucocutaneous leishmaniasis may lead to perforation of the nasal septum, destruction of the mouth, and life-threatening airway obstruction.¹ Determining the specific species is important due to the variation in treatment options and prognosis. Because Leishmania organisms are fastidious, obtaining a positive culture often is challenging. Polymerase chain reaction can be utilized for identification, with detection rates of 97%.¹ Systemic treatment is indicated for patients with multiple or large lesions; lesions on the hands, feet, face, or joints; or immunocompromised patients. Antimonial drugs are the first-line treatment for most forms of leishmaniasis, though increasing resistance has led to a decrease in efficacy.¹ Our patient ultimately was treated with 4 weeks of miltefosine 50 mg 3 times daily. She obtained full resolution of the lesions with no further treatment indicated.

Pemphigus vegetans may present with various clinical manifestations that often can lead to a delay in diagnosis. The Hallopeau subtype typically presents as pustular lesions, while the Neumann subtype may present as large vesiculobullous erosive lesions that rupture and form verrucous, crusted, vegetative plaques. The groin, inguinal folds, axillae, thighs, and flexural areas commonly are affected, but reports of nasal, vaginal, and conjunctival involvement also exist.²

Granuloma inguinale is a sexually transmitted ulcerative disease that is caused by infection with Klebsiella granulomatis. It typically is found in tropical and subtropical climates, including Australia, Brazil, India, and South Africa. The initial presentation includes a single papule or multiple papules or nodules in the genital area that progress to a painless ulcer. It can be diagnosed via biopsies or tissue smears, which will demonstrate the presence of inclusion bodies known as Donovan bodies.³

Cutaneous tuberculosis (TB) can have variable clinical presentations and may be acquired exogenously or endogenously. Cutaneous TB can be divided into 2 categories: exogenous TB caused by inoculation and endogenous TB due to direct spread or autoinoculation. Exogenous TB subtypes include tuberculous chancre and TB verrucosa cutis, while endogenous TB includes scrofuloderma, orificial TB, and lupus vulgaris.⁴ Patches and plaques are found in patients with lupus vulgaris and TB verrucosa cutis. Scrofuloderma, tuberculous chancre, and orificial TB can present as ulcerative or erosive lesions. Cutaneous TB infection can be diagnosed through a smear, culture, or polymerase chain reaction.⁴

Deep cutaneous fungal infections most commonly present in immunocompromised individuals, particularly those who are severely neutropenic and are receiving broad-spectrum systemic antimicrobial agents. Deep cutaneous fungal infections initially present as a papule and evolve into a pustule followed by a necrotic ulcer. The lesions typically are accompanied by a fever and/or vital sign abnormalities.⁵

Verrucous carcinoma (VC) is an uncommon type of well-differentiated squamous cell carcinoma (SCC) that most commonly affects men in the fifth to sixth decades of life. ¹ The tumor grows slowly over a decade or more and does not frequently metastasize but has a high propensity for recurrence and local invasion. ²  There are 3 main subtypes of VC classified by anatomic site: oral florid papillomatosis (oral cavity), Buschke-Lowenstein tumor (anogenital region), and epithelioma cuniculatum (EC)(feet). ³ Epithelioma cuniculatum, also known as carcinoma cuniculatum or papillomatosis cutis carcinoides, most commonly presents as a solitary, warty or cauliflowerlike, exophytic mass with keratin-filled sinus tracts and malodorous discharge. ⁴ Diabetic foot ulcers and chronic inflammatory conditions are predisposing risk factors for EC, and it can result in difficulty walking/immobility, pain, and bleeding depending on anatomic involvement. ^5-9

The differential diagnosis for VC includes refractory verruca vulgaris, clavus, SCC, keratoacanthoma, deep fungal or mycobacterial infection, eccrine poroma or porocarcinoma, amelanotic melanoma, and sarcoma.^10-13 The slow-growing nature of VC, sampling error of superficial biopsies, and minimal cytological atypia on histologic examination can contribute to delayed diagnosis and appropriate treatment.¹⁴ Characteristic histologic features include hyperkeratosis, papillomatosis, marked acanthosis, broad blunt-ended rete ridges with a “bulldozing” architecture, and minimal cytologic atypia and mitoses.^5,6 In some cases, pleomorphism and glassy eosinophilic cytoplasmic changes may be more pronounced than that of a common wart though less dramatic than that of conventional SCCs.¹⁵ Antigen Ki-67 and tumor protein p53 have been proposed to help differentiate between common plantar verruca, VC, and SCC, but the histologic diagnosis remains challenging, and repeat histopathologic examination often is required.^16-19 Following diagnosis, computed tomography or magnetic resonance imaging may be necessary to determine tumor extension and assess for deep tissue and bony involvement.^20-22

Treatment of EC is particularly challenging because of the anatomic location and need for margin control while maintaining adequate function, preserving healthy tissue, and providing coverage of defects. Surgical excision of EC is the first-line treatment, most commonly by wide local excision (WLE) or amputation. Mohs micrographic surgery (MMS) also has been utilized. One review found no recurrences in 5 cases of EC treated with MMS.²³ As MMS is a tissue-sparing technique, this is a valuable modality for sites of functional importance such as the feet. Herein, we review various reported EC treatment modalities and outcomes, with an emphasis on recurrence rates for WLE and MMS.

METHODS

A systematic literature review of PubMed articles indexed for MEDLINE, as well as databases including the Cochrane Library, Web of Science, and Cumulative Index to Nursing and Allied Health Literature (CINAHL), was performed on January 14, 2020. Two authors (S.S.D. and S.V.C.) independently screened results using the search terms (plantar OR foot) AND (verrucous carcinoma OR epithelioma cuniculatum OR carcinoma cuniculatum). The search terms were chosen according to MeSH subject headings. All articles from the start date of the databases through the search date were screened, and articles pertaining to VC, EC, or carcinoma cuniculatum located on the foot were included. Of these, non–English-language articles were translated and included. Articles reporting VC on a site other than the foot (eg, the oral cavity) or benign verrucous skin lesions were excluded. The reference lists for all articles also were reviewed for additional reports that were absent from the initial search using both included and excluded articles. A full-text review was performed on 221 articles published between 1954 and 2019 per the PRISMA guidelines (Figure).

A total of 101 articles were included in the study for qualitative analysis. Nearly all articles identified were case reports, giving an evidence level of 5 by the Centre for Evidence-Based Medicine rating scale. Five articles reported data on multiple patients without individual demographic or clinical details and were excluded from analysis. Of the remaining 96 articles, information about patient characteristics, tumor size, treatment modality, and recurrence were extracted for 115 cases.

RESULTS

Of the 115 cases that were reviewed, 81 (70%) were male and 33 (29%) were female with a male-to-female ratio of 2.4:1. Ages of the patients ranged from 18 to 88 years; the mean and median age was 56 years. Nearly all reported cases of EC affected the plantar surface of one foot, with 4 reports of tumors affecting both feet.^24-27 One case affecting both feet reported known exposure to lead arsenate pesticides²⁷; all others were associated with a clinical history of chronic ulcers or warts persisting for several years to decades. Other less common sites of EC included the dorsal foot, interdigital web space, and subungual digit.^28-30 The most common location reported was the anterior ball of the foot. Tumors were reported to arise within pre-existing lesions, such as hypertrophic lichen planus or chronic foot wounds associated with diabetes mellitus or leprosy.^31-35 Tumor size ranged from 1 to 22 cm with a median of 4.5 cm.

Eight cases were reported to be associated with human papillomavirus; low-risk types 6 and 11 and high-risk types 16 and 18 were found in 6 cases.^36-41 Two cases reported association with human papillomavirus type 2.^7,42

Metastases to dermal and subdermal lymphatics, regional lymph nodes, and the lungs were reported in 3 cases, repectively.^43-45 Of these, one primary tumor had received low-dose irradiation in the form of X-ray therapy.⁴⁵

Treatment Modalities

The cases of EC that we reviewed included treatment with surgical and systemic therapies as well as other modalities such as acitretin, interferon alfa, topical imiquimod, curettage, debridement, electrodesiccation, and radiation. The Table includes a complete summary of the treatments we analyzed.

Surgical Therapy—The majority (91% [105/115]) of cases were treated surgically. The most common treatment modality was WLE (50% [58/115]), followed by amputation (37% [43/115]) and MMS (12% [14/115]).

Wide local excision was the most frequently reported treatment, with excision margins of at least 5 mm to 1 cm.⁴⁸ Incidence of recurrence was reported for 57% (33/58) of cases treated with WLE; of these, the recurrence rate was 33% (11/33). For patients with EC recurrence, the most common secondary treatment was repeat excision with wider margins (1–2 cm) or amputation (5/11).^49-52 Few postoperative complications were reported but included pain, infection, and difficulty walking, which were mostly associated with repair modality (eg, split-thickness skin grafts, rotational flaps).⁵³ 
Amputation was the second most common treatment modality, with a 67% (29/43) incidence of recurrence. Types of amputation included transmetatarsal ray amputation (7/43 [16%]), foot or forefoot amputation (2/43 [5%]), above-the-knee amputation (1/43 [2%]), and below-the-knee amputation (1/43 [2%]). Complications associated with amputation included infection and requirement of prosthetics for ambulation. Split-thickness skin grafts and rotational flaps were the most common surgical repairs performed.^52,53

Mohs micrographic surgery was the least frequently reported surgical treatment modality. Both traditional MMS on fresh tissue and “slow Mohs,” with formalin-fixed paraffin embedded tissue examination over several days, were performed for EC with horizontal en face sectioning.^54-56 Incidence of recurrence was reported for 86% (12/14) of MMS cases. Of these, recurrence was seen in 17% (2/12) that utilized a flat horizontal processing of tissue sections coupled with saucerlike excisions to enable examination of the entire undersurface and margins. In one case, the patient was treated with MMS with recurrence noted 1 month later; thus, repeat MMS was performed, and the tumor was found to be entwined around the flexor tendon.⁵⁷ The tendon was removed, and clear margins were obtained. Follow-up 3 years after the second MMS revealed no signs of recurrence.⁵⁷ In the other case, the patient had a particularly aggressive course with bilateral VC in the setting of diabetic ulcers that was treated with WLE prior to MMS and recurrence still noted after MMS.²⁶ No complications were reported with MMS.

Overall, recurrence was most frequently reported with WLE (11/33 [33%]), followed by MMS (2/12 [17%]) and amputation (3/29 [10%]). When comparing WLE and amputation, the relationship between treatment modality and recurrence was statistically significant using a χ² test of independence (χ²=4.7; P=.03). However, results were not significant with Yates correction for continuity (χ²=3.4; P=.06). The χ² test of independence showed no significant association between treatment method and recurrence when comparing WLE with MMS (χ²=1.2; P=.28). Reported follow-up times varied greatly from a few months to 10 years.

Systemic Therapy—Of the total cases, only 2 cases reported treatment with acitretin and 2 utilized interferon alfa.^58,59 In one case, treatment of EC with interferon alfa alone required more aggressive therapy (ie, amputation).⁵⁸ Neither of the 2 cases using acitretin reported recurrence.^59,60 Complications of acitretin therapy included cheilitis and transaminitis.⁶⁰

Other Treatment Modalities—Three cases utilized imiquimod, with 2 cases of imiquimod monotherapy and 1 case of imiquimod in combination with electrodesiccation and WLE.³⁷ One of the cases of EC treated with imiquimod monotherapy recurred and required WLE.⁶¹

There were reports of other treatments including curettage alone (2% [2/115]),^40,62 debridement alone (1% [1/115]),⁴⁰ electrodesiccation (1% [1/115]),³⁷ and radiation (1% [1/115]).⁴³ Recurrence was found with curettage alone and debridement alone. Electrodesiccation was reported in conjunction with WLE without recurrence. Radiation was used to treat a case of VC that had metastasized to the lymph nodes; no follow-up was described.⁴³

COMMENT

Epithelioma cuniculatum is an indolent malignancy of the plantar foot that likely is frequently underdiagnosed or misdiagnosed because of location, sampling error, and challenges in histopathologic diagnosis. Once diagnosed, surgical removal with margin control is the first-line therapy for EC. Our review found a number of surgical, systemic, and other treatment modalities that have been used to treat EC, but there remains a lack of evidence to provide clear guidelines as to which therapies are most effective. Current data on the treatment of EC largely are limited to case reports and case series. To date, there are no reports of higher-quality studies or randomized controlled trials to assess the efficacy of various treatment modalities.

Our review found that WLE is the most common treatment modality for EC, followed by amputation and MMS. Three cases^43-45 that reported metastasis to lymph nodes also were treated with fine-needle aspiration or biopsy, and it is recommended that sentinel lymph node biopsy be performed when there is a history of radiation exposure or clinically and sonographically unsuspicious lymph nodes, while dissection of regional nodes should be performed if lymph node metastasis is suspected.⁵³ Additional treatments reported included acitretin, interferon alfa, topical imiquimod, curettage, debridement, and electrodesiccation, but because of the limited number of cases and variable efficacy, no conclusions can be made on the utility of these alternative modalities.

The lowest rate of reported recurrence was found with amputation, followed by MMS and WLE. Amputation is the most aggressive treatment option, but its superiority in lower recurrence rates was not statistically significant when compared with either WLE or MMS after Yates correction. Despite treatment with radical surgery, recurrence is still possible and may be associated with factors including greater size (>2 cm) and depth (>4 mm), poor histologic differentiation, perineural involvement, failure of previous treatments, and immunosuppression.⁶³ No statistically significant difference in recurrence rates was found among surgical methods, though data trended toward lower rates of recurrence with MMS compared with WLE, as recurrence with MMS was only reported in 2 cases.^25,56

The efficacy of MMS is well documented for tumors with contiguous growth and enables maximum preservation of normal tissue structure and function with complete margin visualization. Thus, our results are in agreement with those of prior studies,^54-56,64 suggesting that MMS is associated with lower recurrence rates for EC than WLE. Future studies and reporting of MMS for EC are particularly important because of the functional importance of the plantar foot.

It is important to note that there are local and systemic risk factors that increase the likelihood of developing EC and facilitate tumor growth, including antecedent trauma to the lesion site, chronic irritation or infection, and immunosuppression (HIV related or iatrogenic medication induced). These risk factors may play a role in the treatment modality utilized (eg, more aggressive EC may be treated with amputation instead of WLE). Underlying patient comorbidities could potentially affect recurrence rates, which is a variable we could not control for in our analysis.

Our findings are limited by study design, with supporting evidence consisting of case reports and series. The review is limited by interstudy variability and heterogeneity of results. Additionally, recurrence is not reported in all cases and may be a source of sampling bias. Further complicating the generalizability of these results is the lack of follow-up to evaluate morbidity and quality of life after treatment.

CONCLUSION

This review suggests that MMS is associated with lower recurrence rates than WLE for the treatment of EC. Further investigation of MMS for EC with appropriate follow-up is necessary to identify whether MMS is associated with lower recurrence and less functional impairment. Nonsurgical treatments, including topical imiquimod, interferon alfa, and acitretin, may be useful in cases where surgical therapies are contraindicated, but there is little evidence to support these treatment modalities. Treatment guidelines for EC are not established, and appropriate treatment guidelines should be developed in the future.

Verrucous carcinoma (VC) is an uncommon type of well-differentiated squamous cell carcinoma (SCC) that most commonly affects men in the fifth to sixth decades of life. ¹ The tumor grows slowly over a decade or more and does not frequently metastasize but has a high propensity for recurrence and local invasion. ²  There are 3 main subtypes of VC classified by anatomic site: oral florid papillomatosis (oral cavity), Buschke-Lowenstein tumor (anogenital region), and epithelioma cuniculatum (EC)(feet). ³ Epithelioma cuniculatum, also known as carcinoma cuniculatum or papillomatosis cutis carcinoides, most commonly presents as a solitary, warty or cauliflowerlike, exophytic mass with keratin-filled sinus tracts and malodorous discharge. ⁴ Diabetic foot ulcers and chronic inflammatory conditions are predisposing risk factors for EC, and it can result in difficulty walking/immobility, pain, and bleeding depending on anatomic involvement. ^5-9

The differential diagnosis for VC includes refractory verruca vulgaris, clavus, SCC, keratoacanthoma, deep fungal or mycobacterial infection, eccrine poroma or porocarcinoma, amelanotic melanoma, and sarcoma.^10-13 The slow-growing nature of VC, sampling error of superficial biopsies, and minimal cytological atypia on histologic examination can contribute to delayed diagnosis and appropriate treatment.¹⁴ Characteristic histologic features include hyperkeratosis, papillomatosis, marked acanthosis, broad blunt-ended rete ridges with a “bulldozing” architecture, and minimal cytologic atypia and mitoses.^5,6 In some cases, pleomorphism and glassy eosinophilic cytoplasmic changes may be more pronounced than that of a common wart though less dramatic than that of conventional SCCs.¹⁵ Antigen Ki-67 and tumor protein p53 have been proposed to help differentiate between common plantar verruca, VC, and SCC, but the histologic diagnosis remains challenging, and repeat histopathologic examination often is required.^16-19 Following diagnosis, computed tomography or magnetic resonance imaging may be necessary to determine tumor extension and assess for deep tissue and bony involvement.^20-22

Treatment of EC is particularly challenging because of the anatomic location and need for margin control while maintaining adequate function, preserving healthy tissue, and providing coverage of defects. Surgical excision of EC is the first-line treatment, most commonly by wide local excision (WLE) or amputation. Mohs micrographic surgery (MMS) also has been utilized. One review found no recurrences in 5 cases of EC treated with MMS.²³ As MMS is a tissue-sparing technique, this is a valuable modality for sites of functional importance such as the feet. Herein, we review various reported EC treatment modalities and outcomes, with an emphasis on recurrence rates for WLE and MMS.

METHODS

A systematic literature review of PubMed articles indexed for MEDLINE, as well as databases including the Cochrane Library, Web of Science, and Cumulative Index to Nursing and Allied Health Literature (CINAHL), was performed on January 14, 2020. Two authors (S.S.D. and S.V.C.) independently screened results using the search terms (plantar OR foot) AND (verrucous carcinoma OR epithelioma cuniculatum OR carcinoma cuniculatum). The search terms were chosen according to MeSH subject headings. All articles from the start date of the databases through the search date were screened, and articles pertaining to VC, EC, or carcinoma cuniculatum located on the foot were included. Of these, non–English-language articles were translated and included. Articles reporting VC on a site other than the foot (eg, the oral cavity) or benign verrucous skin lesions were excluded. The reference lists for all articles also were reviewed for additional reports that were absent from the initial search using both included and excluded articles. A full-text review was performed on 221 articles published between 1954 and 2019 per the PRISMA guidelines (Figure).

A total of 101 articles were included in the study for qualitative analysis. Nearly all articles identified were case reports, giving an evidence level of 5 by the Centre for Evidence-Based Medicine rating scale. Five articles reported data on multiple patients without individual demographic or clinical details and were excluded from analysis. Of the remaining 96 articles, information about patient characteristics, tumor size, treatment modality, and recurrence were extracted for 115 cases.

RESULTS

Of the 115 cases that were reviewed, 81 (70%) were male and 33 (29%) were female with a male-to-female ratio of 2.4:1. Ages of the patients ranged from 18 to 88 years; the mean and median age was 56 years. Nearly all reported cases of EC affected the plantar surface of one foot, with 4 reports of tumors affecting both feet.^24-27 One case affecting both feet reported known exposure to lead arsenate pesticides²⁷; all others were associated with a clinical history of chronic ulcers or warts persisting for several years to decades. Other less common sites of EC included the dorsal foot, interdigital web space, and subungual digit.^28-30 The most common location reported was the anterior ball of the foot. Tumors were reported to arise within pre-existing lesions, such as hypertrophic lichen planus or chronic foot wounds associated with diabetes mellitus or leprosy.^31-35 Tumor size ranged from 1 to 22 cm with a median of 4.5 cm.

Eight cases were reported to be associated with human papillomavirus; low-risk types 6 and 11 and high-risk types 16 and 18 were found in 6 cases.^36-41 Two cases reported association with human papillomavirus type 2.^7,42

Metastases to dermal and subdermal lymphatics, regional lymph nodes, and the lungs were reported in 3 cases, repectively.^43-45 Of these, one primary tumor had received low-dose irradiation in the form of X-ray therapy.⁴⁵

Treatment Modalities

The cases of EC that we reviewed included treatment with surgical and systemic therapies as well as other modalities such as acitretin, interferon alfa, topical imiquimod, curettage, debridement, electrodesiccation, and radiation. The Table includes a complete summary of the treatments we analyzed.

Surgical Therapy—The majority (91% [105/115]) of cases were treated surgically. The most common treatment modality was WLE (50% [58/115]), followed by amputation (37% [43/115]) and MMS (12% [14/115]).

Wide local excision was the most frequently reported treatment, with excision margins of at least 5 mm to 1 cm.⁴⁸ Incidence of recurrence was reported for 57% (33/58) of cases treated with WLE; of these, the recurrence rate was 33% (11/33). For patients with EC recurrence, the most common secondary treatment was repeat excision with wider margins (1–2 cm) or amputation (5/11).^49-52 Few postoperative complications were reported but included pain, infection, and difficulty walking, which were mostly associated with repair modality (eg, split-thickness skin grafts, rotational flaps).⁵³ 
Amputation was the second most common treatment modality, with a 67% (29/43) incidence of recurrence. Types of amputation included transmetatarsal ray amputation (7/43 [16%]), foot or forefoot amputation (2/43 [5%]), above-the-knee amputation (1/43 [2%]), and below-the-knee amputation (1/43 [2%]). Complications associated with amputation included infection and requirement of prosthetics for ambulation. Split-thickness skin grafts and rotational flaps were the most common surgical repairs performed.^52,53

Mohs micrographic surgery was the least frequently reported surgical treatment modality. Both traditional MMS on fresh tissue and “slow Mohs,” with formalin-fixed paraffin embedded tissue examination over several days, were performed for EC with horizontal en face sectioning.^54-56 Incidence of recurrence was reported for 86% (12/14) of MMS cases. Of these, recurrence was seen in 17% (2/12) that utilized a flat horizontal processing of tissue sections coupled with saucerlike excisions to enable examination of the entire undersurface and margins. In one case, the patient was treated with MMS with recurrence noted 1 month later; thus, repeat MMS was performed, and the tumor was found to be entwined around the flexor tendon.⁵⁷ The tendon was removed, and clear margins were obtained. Follow-up 3 years after the second MMS revealed no signs of recurrence.⁵⁷ In the other case, the patient had a particularly aggressive course with bilateral VC in the setting of diabetic ulcers that was treated with WLE prior to MMS and recurrence still noted after MMS.²⁶ No complications were reported with MMS.

Overall, recurrence was most frequently reported with WLE (11/33 [33%]), followed by MMS (2/12 [17%]) and amputation (3/29 [10%]). When comparing WLE and amputation, the relationship between treatment modality and recurrence was statistically significant using a χ² test of independence (χ²=4.7; P=.03). However, results were not significant with Yates correction for continuity (χ²=3.4; P=.06). The χ² test of independence showed no significant association between treatment method and recurrence when comparing WLE with MMS (χ²=1.2; P=.28). Reported follow-up times varied greatly from a few months to 10 years.

Systemic Therapy—Of the total cases, only 2 cases reported treatment with acitretin and 2 utilized interferon alfa.^58,59 In one case, treatment of EC with interferon alfa alone required more aggressive therapy (ie, amputation).⁵⁸ Neither of the 2 cases using acitretin reported recurrence.^59,60 Complications of acitretin therapy included cheilitis and transaminitis.⁶⁰

Other Treatment Modalities—Three cases utilized imiquimod, with 2 cases of imiquimod monotherapy and 1 case of imiquimod in combination with electrodesiccation and WLE.³⁷ One of the cases of EC treated with imiquimod monotherapy recurred and required WLE.⁶¹

There were reports of other treatments including curettage alone (2% [2/115]),^40,62 debridement alone (1% [1/115]),⁴⁰ electrodesiccation (1% [1/115]),³⁷ and radiation (1% [1/115]).⁴³ Recurrence was found with curettage alone and debridement alone. Electrodesiccation was reported in conjunction with WLE without recurrence. Radiation was used to treat a case of VC that had metastasized to the lymph nodes; no follow-up was described.⁴³

COMMENT

Epithelioma cuniculatum is an indolent malignancy of the plantar foot that likely is frequently underdiagnosed or misdiagnosed because of location, sampling error, and challenges in histopathologic diagnosis. Once diagnosed, surgical removal with margin control is the first-line therapy for EC. Our review found a number of surgical, systemic, and other treatment modalities that have been used to treat EC, but there remains a lack of evidence to provide clear guidelines as to which therapies are most effective. Current data on the treatment of EC largely are limited to case reports and case series. To date, there are no reports of higher-quality studies or randomized controlled trials to assess the efficacy of various treatment modalities.

Our review found that WLE is the most common treatment modality for EC, followed by amputation and MMS. Three cases^43-45 that reported metastasis to lymph nodes also were treated with fine-needle aspiration or biopsy, and it is recommended that sentinel lymph node biopsy be performed when there is a history of radiation exposure or clinically and sonographically unsuspicious lymph nodes, while dissection of regional nodes should be performed if lymph node metastasis is suspected.⁵³ Additional treatments reported included acitretin, interferon alfa, topical imiquimod, curettage, debridement, and electrodesiccation, but because of the limited number of cases and variable efficacy, no conclusions can be made on the utility of these alternative modalities.

The lowest rate of reported recurrence was found with amputation, followed by MMS and WLE. Amputation is the most aggressive treatment option, but its superiority in lower recurrence rates was not statistically significant when compared with either WLE or MMS after Yates correction. Despite treatment with radical surgery, recurrence is still possible and may be associated with factors including greater size (>2 cm) and depth (>4 mm), poor histologic differentiation, perineural involvement, failure of previous treatments, and immunosuppression.⁶³ No statistically significant difference in recurrence rates was found among surgical methods, though data trended toward lower rates of recurrence with MMS compared with WLE, as recurrence with MMS was only reported in 2 cases.^25,56

The efficacy of MMS is well documented for tumors with contiguous growth and enables maximum preservation of normal tissue structure and function with complete margin visualization. Thus, our results are in agreement with those of prior studies,^54-56,64 suggesting that MMS is associated with lower recurrence rates for EC than WLE. Future studies and reporting of MMS for EC are particularly important because of the functional importance of the plantar foot.

It is important to note that there are local and systemic risk factors that increase the likelihood of developing EC and facilitate tumor growth, including antecedent trauma to the lesion site, chronic irritation or infection, and immunosuppression (HIV related or iatrogenic medication induced). These risk factors may play a role in the treatment modality utilized (eg, more aggressive EC may be treated with amputation instead of WLE). Underlying patient comorbidities could potentially affect recurrence rates, which is a variable we could not control for in our analysis.

Our findings are limited by study design, with supporting evidence consisting of case reports and series. The review is limited by interstudy variability and heterogeneity of results. Additionally, recurrence is not reported in all cases and may be a source of sampling bias. Further complicating the generalizability of these results is the lack of follow-up to evaluate morbidity and quality of life after treatment.

CONCLUSION

This review suggests that MMS is associated with lower recurrence rates than WLE for the treatment of EC. Further investigation of MMS for EC with appropriate follow-up is necessary to identify whether MMS is associated with lower recurrence and less functional impairment. Nonsurgical treatments, including topical imiquimod, interferon alfa, and acitretin, may be useful in cases where surgical therapies are contraindicated, but there is little evidence to support these treatment modalities. Treatment guidelines for EC are not established, and appropriate treatment guidelines should be developed in the future.

Verrucous carcinoma (VC) is an uncommon type of well-differentiated squamous cell carcinoma (SCC) that most commonly affects men in the fifth to sixth decades of life. ¹ The tumor grows slowly over a decade or more and does not frequently metastasize but has a high propensity for recurrence and local invasion. ²  There are 3 main subtypes of VC classified by anatomic site: oral florid papillomatosis (oral cavity), Buschke-Lowenstein tumor (anogenital region), and epithelioma cuniculatum (EC)(feet). ³ Epithelioma cuniculatum, also known as carcinoma cuniculatum or papillomatosis cutis carcinoides, most commonly presents as a solitary, warty or cauliflowerlike, exophytic mass with keratin-filled sinus tracts and malodorous discharge. ⁴ Diabetic foot ulcers and chronic inflammatory conditions are predisposing risk factors for EC, and it can result in difficulty walking/immobility, pain, and bleeding depending on anatomic involvement. ^5-9

The differential diagnosis for VC includes refractory verruca vulgaris, clavus, SCC, keratoacanthoma, deep fungal or mycobacterial infection, eccrine poroma or porocarcinoma, amelanotic melanoma, and sarcoma.^10-13 The slow-growing nature of VC, sampling error of superficial biopsies, and minimal cytological atypia on histologic examination can contribute to delayed diagnosis and appropriate treatment.¹⁴ Characteristic histologic features include hyperkeratosis, papillomatosis, marked acanthosis, broad blunt-ended rete ridges with a “bulldozing” architecture, and minimal cytologic atypia and mitoses.^5,6 In some cases, pleomorphism and glassy eosinophilic cytoplasmic changes may be more pronounced than that of a common wart though less dramatic than that of conventional SCCs.¹⁵ Antigen Ki-67 and tumor protein p53 have been proposed to help differentiate between common plantar verruca, VC, and SCC, but the histologic diagnosis remains challenging, and repeat histopathologic examination often is required.^16-19 Following diagnosis, computed tomography or magnetic resonance imaging may be necessary to determine tumor extension and assess for deep tissue and bony involvement.^20-22

Treatment of EC is particularly challenging because of the anatomic location and need for margin control while maintaining adequate function, preserving healthy tissue, and providing coverage of defects. Surgical excision of EC is the first-line treatment, most commonly by wide local excision (WLE) or amputation. Mohs micrographic surgery (MMS) also has been utilized. One review found no recurrences in 5 cases of EC treated with MMS.²³ As MMS is a tissue-sparing technique, this is a valuable modality for sites of functional importance such as the feet. Herein, we review various reported EC treatment modalities and outcomes, with an emphasis on recurrence rates for WLE and MMS.

METHODS

A systematic literature review of PubMed articles indexed for MEDLINE, as well as databases including the Cochrane Library, Web of Science, and Cumulative Index to Nursing and Allied Health Literature (CINAHL), was performed on January 14, 2020. Two authors (S.S.D. and S.V.C.) independently screened results using the search terms (plantar OR foot) AND (verrucous carcinoma OR epithelioma cuniculatum OR carcinoma cuniculatum). The search terms were chosen according to MeSH subject headings. All articles from the start date of the databases through the search date were screened, and articles pertaining to VC, EC, or carcinoma cuniculatum located on the foot were included. Of these, non–English-language articles were translated and included. Articles reporting VC on a site other than the foot (eg, the oral cavity) or benign verrucous skin lesions were excluded. The reference lists for all articles also were reviewed for additional reports that were absent from the initial search using both included and excluded articles. A full-text review was performed on 221 articles published between 1954 and 2019 per the PRISMA guidelines (Figure).

A total of 101 articles were included in the study for qualitative analysis. Nearly all articles identified were case reports, giving an evidence level of 5 by the Centre for Evidence-Based Medicine rating scale. Five articles reported data on multiple patients without individual demographic or clinical details and were excluded from analysis. Of the remaining 96 articles, information about patient characteristics, tumor size, treatment modality, and recurrence were extracted for 115 cases.

RESULTS

Of the 115 cases that were reviewed, 81 (70%) were male and 33 (29%) were female with a male-to-female ratio of 2.4:1. Ages of the patients ranged from 18 to 88 years; the mean and median age was 56 years. Nearly all reported cases of EC affected the plantar surface of one foot, with 4 reports of tumors affecting both feet.^24-27 One case affecting both feet reported known exposure to lead arsenate pesticides²⁷; all others were associated with a clinical history of chronic ulcers or warts persisting for several years to decades. Other less common sites of EC included the dorsal foot, interdigital web space, and subungual digit.^28-30 The most common location reported was the anterior ball of the foot. Tumors were reported to arise within pre-existing lesions, such as hypertrophic lichen planus or chronic foot wounds associated with diabetes mellitus or leprosy.^31-35 Tumor size ranged from 1 to 22 cm with a median of 4.5 cm.

Eight cases were reported to be associated with human papillomavirus; low-risk types 6 and 11 and high-risk types 16 and 18 were found in 6 cases.^36-41 Two cases reported association with human papillomavirus type 2.^7,42

Metastases to dermal and subdermal lymphatics, regional lymph nodes, and the lungs were reported in 3 cases, repectively.^43-45 Of these, one primary tumor had received low-dose irradiation in the form of X-ray therapy.⁴⁵

Treatment Modalities

The cases of EC that we reviewed included treatment with surgical and systemic therapies as well as other modalities such as acitretin, interferon alfa, topical imiquimod, curettage, debridement, electrodesiccation, and radiation. The Table includes a complete summary of the treatments we analyzed.

Surgical Therapy—The majority (91% [105/115]) of cases were treated surgically. The most common treatment modality was WLE (50% [58/115]), followed by amputation (37% [43/115]) and MMS (12% [14/115]).

Wide local excision was the most frequently reported treatment, with excision margins of at least 5 mm to 1 cm.⁴⁸ Incidence of recurrence was reported for 57% (33/58) of cases treated with WLE; of these, the recurrence rate was 33% (11/33). For patients with EC recurrence, the most common secondary treatment was repeat excision with wider margins (1–2 cm) or amputation (5/11).^49-52 Few postoperative complications were reported but included pain, infection, and difficulty walking, which were mostly associated with repair modality (eg, split-thickness skin grafts, rotational flaps).⁵³ 
Amputation was the second most common treatment modality, with a 67% (29/43) incidence of recurrence. Types of amputation included transmetatarsal ray amputation (7/43 [16%]), foot or forefoot amputation (2/43 [5%]), above-the-knee amputation (1/43 [2%]), and below-the-knee amputation (1/43 [2%]). Complications associated with amputation included infection and requirement of prosthetics for ambulation. Split-thickness skin grafts and rotational flaps were the most common surgical repairs performed.^52,53

Mohs micrographic surgery was the least frequently reported surgical treatment modality. Both traditional MMS on fresh tissue and “slow Mohs,” with formalin-fixed paraffin embedded tissue examination over several days, were performed for EC with horizontal en face sectioning.^54-56 Incidence of recurrence was reported for 86% (12/14) of MMS cases. Of these, recurrence was seen in 17% (2/12) that utilized a flat horizontal processing of tissue sections coupled with saucerlike excisions to enable examination of the entire undersurface and margins. In one case, the patient was treated with MMS with recurrence noted 1 month later; thus, repeat MMS was performed, and the tumor was found to be entwined around the flexor tendon.⁵⁷ The tendon was removed, and clear margins were obtained. Follow-up 3 years after the second MMS revealed no signs of recurrence.⁵⁷ In the other case, the patient had a particularly aggressive course with bilateral VC in the setting of diabetic ulcers that was treated with WLE prior to MMS and recurrence still noted after MMS.²⁶ No complications were reported with MMS.

Overall, recurrence was most frequently reported with WLE (11/33 [33%]), followed by MMS (2/12 [17%]) and amputation (3/29 [10%]). When comparing WLE and amputation, the relationship between treatment modality and recurrence was statistically significant using a χ² test of independence (χ²=4.7; P=.03). However, results were not significant with Yates correction for continuity (χ²=3.4; P=.06). The χ² test of independence showed no significant association between treatment method and recurrence when comparing WLE with MMS (χ²=1.2; P=.28). Reported follow-up times varied greatly from a few months to 10 years.

Systemic Therapy—Of the total cases, only 2 cases reported treatment with acitretin and 2 utilized interferon alfa.^58,59 In one case, treatment of EC with interferon alfa alone required more aggressive therapy (ie, amputation).⁵⁸ Neither of the 2 cases using acitretin reported recurrence.^59,60 Complications of acitretin therapy included cheilitis and transaminitis.⁶⁰

Other Treatment Modalities—Three cases utilized imiquimod, with 2 cases of imiquimod monotherapy and 1 case of imiquimod in combination with electrodesiccation and WLE.³⁷ One of the cases of EC treated with imiquimod monotherapy recurred and required WLE.⁶¹

There were reports of other treatments including curettage alone (2% [2/115]),^40,62 debridement alone (1% [1/115]),⁴⁰ electrodesiccation (1% [1/115]),³⁷ and radiation (1% [1/115]).⁴³ Recurrence was found with curettage alone and debridement alone. Electrodesiccation was reported in conjunction with WLE without recurrence. Radiation was used to treat a case of VC that had metastasized to the lymph nodes; no follow-up was described.⁴³

COMMENT

Epithelioma cuniculatum is an indolent malignancy of the plantar foot that likely is frequently underdiagnosed or misdiagnosed because of location, sampling error, and challenges in histopathologic diagnosis. Once diagnosed, surgical removal with margin control is the first-line therapy for EC. Our review found a number of surgical, systemic, and other treatment modalities that have been used to treat EC, but there remains a lack of evidence to provide clear guidelines as to which therapies are most effective. Current data on the treatment of EC largely are limited to case reports and case series. To date, there are no reports of higher-quality studies or randomized controlled trials to assess the efficacy of various treatment modalities.

Our review found that WLE is the most common treatment modality for EC, followed by amputation and MMS. Three cases^43-45 that reported metastasis to lymph nodes also were treated with fine-needle aspiration or biopsy, and it is recommended that sentinel lymph node biopsy be performed when there is a history of radiation exposure or clinically and sonographically unsuspicious lymph nodes, while dissection of regional nodes should be performed if lymph node metastasis is suspected.⁵³ Additional treatments reported included acitretin, interferon alfa, topical imiquimod, curettage, debridement, and electrodesiccation, but because of the limited number of cases and variable efficacy, no conclusions can be made on the utility of these alternative modalities.

The lowest rate of reported recurrence was found with amputation, followed by MMS and WLE. Amputation is the most aggressive treatment option, but its superiority in lower recurrence rates was not statistically significant when compared with either WLE or MMS after Yates correction. Despite treatment with radical surgery, recurrence is still possible and may be associated with factors including greater size (>2 cm) and depth (>4 mm), poor histologic differentiation, perineural involvement, failure of previous treatments, and immunosuppression.⁶³ No statistically significant difference in recurrence rates was found among surgical methods, though data trended toward lower rates of recurrence with MMS compared with WLE, as recurrence with MMS was only reported in 2 cases.^25,56

The efficacy of MMS is well documented for tumors with contiguous growth and enables maximum preservation of normal tissue structure and function with complete margin visualization. Thus, our results are in agreement with those of prior studies,^54-56,64 suggesting that MMS is associated with lower recurrence rates for EC than WLE. Future studies and reporting of MMS for EC are particularly important because of the functional importance of the plantar foot.

It is important to note that there are local and systemic risk factors that increase the likelihood of developing EC and facilitate tumor growth, including antecedent trauma to the lesion site, chronic irritation or infection, and immunosuppression (HIV related or iatrogenic medication induced). These risk factors may play a role in the treatment modality utilized (eg, more aggressive EC may be treated with amputation instead of WLE). Underlying patient comorbidities could potentially affect recurrence rates, which is a variable we could not control for in our analysis.

Our findings are limited by study design, with supporting evidence consisting of case reports and series. The review is limited by interstudy variability and heterogeneity of results. Additionally, recurrence is not reported in all cases and may be a source of sampling bias. Further complicating the generalizability of these results is the lack of follow-up to evaluate morbidity and quality of life after treatment.

CONCLUSION

This review suggests that MMS is associated with lower recurrence rates than WLE for the treatment of EC. Further investigation of MMS for EC with appropriate follow-up is necessary to identify whether MMS is associated with lower recurrence and less functional impairment. Nonsurgical treatments, including topical imiquimod, interferon alfa, and acitretin, may be useful in cases where surgical therapies are contraindicated, but there is little evidence to support these treatment modalities. Treatment guidelines for EC are not established, and appropriate treatment guidelines should be developed in the future.

Hair loss is an exceedingly common chief concern in outpatient dermatology clinics. An estimated 50% of males and females will experience androgenetic alopecia.¹ Approximately 2% of new dermatology outpatient visits in the United States and the United Kingdom are for alopecia areata, the second most common type of hair loss.² As access to dermatology appointments remains an issue with some studies citing wait times ranging from 2 to 25 days for a dermatologic consultation, the ease of accessibility of medical information on social media continues to grow,³ which leaves many of our patients turning to social media as a first-line source of information. As dermatology resident physicians, it is essential to be aware of popular dermatologic therapies on social media so that we may provide evidence-based opinions to our patients.

Remedies for Hair Loss on Social Media

Many trends on hair loss therapies found on TikTok focus on natural remedies that are produced by ingredients accessible to patients at home and over the counter, which may increase the appeal due to ease of treatment.

Rosemary Oil—The top trends in hair loss remedies I have come across are rosemary oil and rosemary water. Rosemary (Rosmarinus officinalis) has been known to possess antimicrobial and antioxidant properties but also has shown enhancement of microcapillary perfusion, which could explain its role in the prevention of hair loss and aiding hair growth in a similar mechanism to minoxidil.^4,5 Unlike many other natural hair loss remedies, there are randomized controlled trials that assess the efficacy of rosemary oil for the treatment of hair loss. In a 2015 study of 100 patients with androgenetic alopecia,there was no statistically significant difference in mean hair count measured by microphotographic assessment after 6 months of treatment in 2 groups treated with either minoxidil solution 2% or rosemary oil, and both groups experienced a significant increase in hair count at 6 months (P<.05) compared with baseline and 3 months.⁶ Additionally, essential oils, including a mixture of thyme, rosemary, lavender, and cedarwood oils for alopecia were superior to placebo carrier oils in a posttreatment photographic assessment of their efficacy.⁷

Rice Water—The use of rice water and rice bran extract is a common hair care practice in Asia. Rice bran extract preparations have been shown in vivo to increase the number of anagen hair follicles as well as the number of anagen-related molecules in the dermal papillae.^8,9 However, there are limited clinical data to support the use of rice water for hair growth.¹⁰

Onion Juice—Sharquie and Al-Obaidi¹¹ conducted a study comparing crude onion juice to tap water in 38 patients with alopecia areata. They found that onion juice produced hair regrowth in significantly more patients than tap water (P<.0001).¹¹ The mechanism of crude onion juice in hair growth is unknown; however, the induction of irritant or allergic contact dermatitis to components in crude onion juice may stimulate antigenic competition.¹²

Garlic Gel—Garlic gel, which is in the genus Allium, produces organosulfur compounds that provide antimicrobial and anti-inflammatory benefits.¹² Additionally, in a double-blind randomized controlled trial, garlic powder was shown to increase cutaneous capillary perfusion.⁵ One study in 40 patients with alopecia areata demonstrated garlic gel 5% added to betamethasone valerate cream 0.1% was statistically superior to betamethasone alone in stimulating terminal hair growth (P=.001).¹³

Limitations and Downsides to Hair Loss Remedies on Social Media

Social media continues to be a prominent source of medical information for our patients, but most sources of hair content on social media are not board-certified dermatologists. A recent review of alopecia-related content found only 4% and 10% of posts were created by medical professionals on Instagram and TikTok, respectively, making misinformation extremely likely.¹⁴ Natural hair loss remedies contrived by TikTok have little clinical evidence to support their claims. Few data are available that compare these treatments to gold-standard hair loss therapies. Additionally, while some of these agents may be beneficial, the lack of standardized dosing may counteract these benefits. For example, videos on rosemary water advise the viewer to boil fresh rosemary sprigs in water and apply the solution to the hair daily with a spray bottle or apply cloves of garlic directly to the scalp, as opposed to a measured and standardized percentage. Some preparations may even induce harm to patients. Over-the-counter oils with added fragrances and natural compounds in onion and garlic may cause contact dermatitis. Finally, by using these products, patients may delay consultation with a board-certified dermatologist, leading to delays in applying evidence-based therapies targeted to specific hair loss subtypes while also incurring unnecessary expenses for these preparations.

Final Thoughts

Hair loss affects a notable portion of the population and is a common chief concern in dermatology clinics. Misinformation on social media continues to grow in prevalence. It is important to be aware of the hair loss remedies that are commonly touted to patients online and the evidence behind them.

Hair loss is an exceedingly common chief concern in outpatient dermatology clinics. An estimated 50% of males and females will experience androgenetic alopecia.¹ Approximately 2% of new dermatology outpatient visits in the United States and the United Kingdom are for alopecia areata, the second most common type of hair loss.² As access to dermatology appointments remains an issue with some studies citing wait times ranging from 2 to 25 days for a dermatologic consultation, the ease of accessibility of medical information on social media continues to grow,³ which leaves many of our patients turning to social media as a first-line source of information. As dermatology resident physicians, it is essential to be aware of popular dermatologic therapies on social media so that we may provide evidence-based opinions to our patients.

Remedies for Hair Loss on Social Media

Many trends on hair loss therapies found on TikTok focus on natural remedies that are produced by ingredients accessible to patients at home and over the counter, which may increase the appeal due to ease of treatment.

Rosemary Oil—The top trends in hair loss remedies I have come across are rosemary oil and rosemary water. Rosemary (Rosmarinus officinalis) has been known to possess antimicrobial and antioxidant properties but also has shown enhancement of microcapillary perfusion, which could explain its role in the prevention of hair loss and aiding hair growth in a similar mechanism to minoxidil.^4,5 Unlike many other natural hair loss remedies, there are randomized controlled trials that assess the efficacy of rosemary oil for the treatment of hair loss. In a 2015 study of 100 patients with androgenetic alopecia,there was no statistically significant difference in mean hair count measured by microphotographic assessment after 6 months of treatment in 2 groups treated with either minoxidil solution 2% or rosemary oil, and both groups experienced a significant increase in hair count at 6 months (P<.05) compared with baseline and 3 months.⁶ Additionally, essential oils, including a mixture of thyme, rosemary, lavender, and cedarwood oils for alopecia were superior to placebo carrier oils in a posttreatment photographic assessment of their efficacy.⁷

Rice Water—The use of rice water and rice bran extract is a common hair care practice in Asia. Rice bran extract preparations have been shown in vivo to increase the number of anagen hair follicles as well as the number of anagen-related molecules in the dermal papillae.^8,9 However, there are limited clinical data to support the use of rice water for hair growth.¹⁰

Onion Juice—Sharquie and Al-Obaidi¹¹ conducted a study comparing crude onion juice to tap water in 38 patients with alopecia areata. They found that onion juice produced hair regrowth in significantly more patients than tap water (P<.0001).¹¹ The mechanism of crude onion juice in hair growth is unknown; however, the induction of irritant or allergic contact dermatitis to components in crude onion juice may stimulate antigenic competition.¹²

Garlic Gel—Garlic gel, which is in the genus Allium, produces organosulfur compounds that provide antimicrobial and anti-inflammatory benefits.¹² Additionally, in a double-blind randomized controlled trial, garlic powder was shown to increase cutaneous capillary perfusion.⁵ One study in 40 patients with alopecia areata demonstrated garlic gel 5% added to betamethasone valerate cream 0.1% was statistically superior to betamethasone alone in stimulating terminal hair growth (P=.001).¹³

Limitations and Downsides to Hair Loss Remedies on Social Media

Social media continues to be a prominent source of medical information for our patients, but most sources of hair content on social media are not board-certified dermatologists. A recent review of alopecia-related content found only 4% and 10% of posts were created by medical professionals on Instagram and TikTok, respectively, making misinformation extremely likely.¹⁴ Natural hair loss remedies contrived by TikTok have little clinical evidence to support their claims. Few data are available that compare these treatments to gold-standard hair loss therapies. Additionally, while some of these agents may be beneficial, the lack of standardized dosing may counteract these benefits. For example, videos on rosemary water advise the viewer to boil fresh rosemary sprigs in water and apply the solution to the hair daily with a spray bottle or apply cloves of garlic directly to the scalp, as opposed to a measured and standardized percentage. Some preparations may even induce harm to patients. Over-the-counter oils with added fragrances and natural compounds in onion and garlic may cause contact dermatitis. Finally, by using these products, patients may delay consultation with a board-certified dermatologist, leading to delays in applying evidence-based therapies targeted to specific hair loss subtypes while also incurring unnecessary expenses for these preparations.

Final Thoughts

Hair loss affects a notable portion of the population and is a common chief concern in dermatology clinics. Misinformation on social media continues to grow in prevalence. It is important to be aware of the hair loss remedies that are commonly touted to patients online and the evidence behind them.

Hair loss is an exceedingly common chief concern in outpatient dermatology clinics. An estimated 50% of males and females will experience androgenetic alopecia.¹ Approximately 2% of new dermatology outpatient visits in the United States and the United Kingdom are for alopecia areata, the second most common type of hair loss.² As access to dermatology appointments remains an issue with some studies citing wait times ranging from 2 to 25 days for a dermatologic consultation, the ease of accessibility of medical information on social media continues to grow,³ which leaves many of our patients turning to social media as a first-line source of information. As dermatology resident physicians, it is essential to be aware of popular dermatologic therapies on social media so that we may provide evidence-based opinions to our patients.

Remedies for Hair Loss on Social Media

Many trends on hair loss therapies found on TikTok focus on natural remedies that are produced by ingredients accessible to patients at home and over the counter, which may increase the appeal due to ease of treatment.

Rosemary Oil—The top trends in hair loss remedies I have come across are rosemary oil and rosemary water. Rosemary (Rosmarinus officinalis) has been known to possess antimicrobial and antioxidant properties but also has shown enhancement of microcapillary perfusion, which could explain its role in the prevention of hair loss and aiding hair growth in a similar mechanism to minoxidil.^4,5 Unlike many other natural hair loss remedies, there are randomized controlled trials that assess the efficacy of rosemary oil for the treatment of hair loss. In a 2015 study of 100 patients with androgenetic alopecia,there was no statistically significant difference in mean hair count measured by microphotographic assessment after 6 months of treatment in 2 groups treated with either minoxidil solution 2% or rosemary oil, and both groups experienced a significant increase in hair count at 6 months (P<.05) compared with baseline and 3 months.⁶ Additionally, essential oils, including a mixture of thyme, rosemary, lavender, and cedarwood oils for alopecia were superior to placebo carrier oils in a posttreatment photographic assessment of their efficacy.⁷

Rice Water—The use of rice water and rice bran extract is a common hair care practice in Asia. Rice bran extract preparations have been shown in vivo to increase the number of anagen hair follicles as well as the number of anagen-related molecules in the dermal papillae.^8,9 However, there are limited clinical data to support the use of rice water for hair growth.¹⁰

Onion Juice—Sharquie and Al-Obaidi¹¹ conducted a study comparing crude onion juice to tap water in 38 patients with alopecia areata. They found that onion juice produced hair regrowth in significantly more patients than tap water (P<.0001).¹¹ The mechanism of crude onion juice in hair growth is unknown; however, the induction of irritant or allergic contact dermatitis to components in crude onion juice may stimulate antigenic competition.¹²

Garlic Gel—Garlic gel, which is in the genus Allium, produces organosulfur compounds that provide antimicrobial and anti-inflammatory benefits.¹² Additionally, in a double-blind randomized controlled trial, garlic powder was shown to increase cutaneous capillary perfusion.⁵ One study in 40 patients with alopecia areata demonstrated garlic gel 5% added to betamethasone valerate cream 0.1% was statistically superior to betamethasone alone in stimulating terminal hair growth (P=.001).¹³

Limitations and Downsides to Hair Loss Remedies on Social Media

Social media continues to be a prominent source of medical information for our patients, but most sources of hair content on social media are not board-certified dermatologists. A recent review of alopecia-related content found only 4% and 10% of posts were created by medical professionals on Instagram and TikTok, respectively, making misinformation extremely likely.¹⁴ Natural hair loss remedies contrived by TikTok have little clinical evidence to support their claims. Few data are available that compare these treatments to gold-standard hair loss therapies. Additionally, while some of these agents may be beneficial, the lack of standardized dosing may counteract these benefits. For example, videos on rosemary water advise the viewer to boil fresh rosemary sprigs in water and apply the solution to the hair daily with a spray bottle or apply cloves of garlic directly to the scalp, as opposed to a measured and standardized percentage. Some preparations may even induce harm to patients. Over-the-counter oils with added fragrances and natural compounds in onion and garlic may cause contact dermatitis. Finally, by using these products, patients may delay consultation with a board-certified dermatologist, leading to delays in applying evidence-based therapies targeted to specific hair loss subtypes while also incurring unnecessary expenses for these preparations.

Final Thoughts

Hair loss affects a notable portion of the population and is a common chief concern in dermatology clinics. Misinformation on social media continues to grow in prevalence. It is important to be aware of the hair loss remedies that are commonly touted to patients online and the evidence behind them.

To the Editor:

Epidermodysplasia verruciformis (EDV) is a rare generalized form of epidermal dysplasia that is linked to certain subtypes of human papillomavirus (HPV) infection and inherited or acquired states of immunodeficiency.^1-3 The inherited form most commonly manifests via autosomal-recessive inactivation of the EVER1 and EVER2 genes that encode integral membrane proteins in the endoplasmic reticulum, though cases of autosomal-dominant and X-linked inheritance have been reported.^1-3 Acquired cases have been reported in patients lacking immunocompetency, including transplant recipients and patients living with HIV.^4-11 We present the case of a patient with HIV-associated EDV who was treated successfully with intralesional Candida albicans antigen, oral acitretin, and cryotherapy.

A 56-year-old man presented for evaluation of several cutaneous lesions that had developed over several months on the neck and over many years on the hands and feet. He had a 16-year history of HIV, Castleman disease, and primary effusion lymphoma in remission that was treated with rituximab, etoposide phosphate, prednisone, vincristine sulfate, cyclophosphamide, and doxorubicin hydrochloride 10 or more years ago. The patient denied pruritus or pain associated with the skin lesions. He was intermittently taking immunosuppressants and antiretrovirals including dolutegravir and emtricitabine-tenofovir for 3 years. Prior treatments of the lesions included cryotherapy and over-the-counter 17% salicylic acid. Physical examination revealed the presence of innumerable, clustered, verrucous, scaly papules on the dorsal and palmoplantar regions of the hands (Figure 1), as well as hypopigmented macules clustered on the neck that morphologically resembled tinea versicolor (Figure 2). The physical examination was otherwise unremarkable.

Complete blood cell counts as well as lipid, liver, and renal function panel results were unremarkable. Laboratory examination also revealed a CD4 cell count of 373/µL (reference range, 320–1900/µL) and an undetectable HIV copy number (<40 copies/mL). A punch biopsy of a hypopigmented macule on the left side of the neck revealed epidermal acanthosis, hypergranulosis, and hyperkeratosis, with blue-gray cytoplasm observed in the keratinocytes (Figure 3). Koilocytes with perinuclear clearing associated with keratinocytes in the upper epidermis were noted. Based on the clinical and histopathologic correlation, acquired EDV was diagnosed.

Given that HIV-associated EDV often is recalcitrant and there is a lack of consistent and effective treatment, the patient initially was prescribed oral acitretin 25 mg/d with intralesional C albicans antigen injected once per month into the lesions along with concurrent cryotherapy. At subsequent monthly follow-ups, the involved areas were notably thinner and flat. The patient reported no remarkable side effects from the systemic retinoid treatment such as abdominal pain, photosensitivity, or headaches, though he did experience mild xerosis. Complete resolution of EDV occurred with multimodal therapy—acitretin, cryotherapy, and intralesional Candida antigen. Palmar verrucae were much improved, and he is currently continuing therapy.

Epidermodysplasia verruciformis is a rare genodermatosis associated with an abnormal susceptibility to cutaneous HPV and can be acquired in immunocompromised patients. Patients with EDV present with a clinically heterogeneous disease that can manifest as hypopigmented, red-brown macules with scaling on the trunk, neck, and extremities, which are morphologically similar to tinea versicolor, or patients can present with flat wartlike papules that are most commonly found on the face, hands, and feet.^2,3 Epidermodysplasia verruciformis can be distinguished from EDV-like eruptions and other generalized verrucoses by its characteristic histologic appearance and by the demonstration of HPV within the lesions, typically subtypes HPV-5 and HPV-8.^1-3 Classic EDV histopathologic findings include mild to moderate acanthosis and hyperkeratosis with enlarged keratinocytes featuring blue-gray cytoplasm and perinuclear halos.¹

The histologic differential diagnosis of EDV is quite broad and includes common verrucae, which may be distinguished by the absence of blue-gray discoloration of the cytoplasm among the individual keratinocytes.¹ Verruca plana and condylomata also may mimic EDV, and patients may present with minimal papillomatosis of the surface epidermis.² Squamous cell carcinoma in situ (SCC-IS) and particularly bowenoid papulosis also may share similar histologic features.² However, in SCC-IS, there typically is full-thickness dysplasia of the epidermis, which is not present in EDV. Nonetheless, EDV is equivalent to SCC-IS in its clinical behavior. Bowenoid papulosis shares similar findings, but lesions generally are located in the genital areas and linked to HPV-16 and HPV-18.² Additional histologic features of EDV have been described in the entity of EDV acanthoma, specifically incidental findings present in association with other cutaneous neoplasms including acantholytic acanthomas, condylomas, intradermal nevi, and seborrheic keratoses.¹²

The pathophysiology of EDV is thought to be specifically associated with patients with immunocompromised conditions. Particular attention has been paid to the association between EDV and HIV. Anselmo et al¹³ reported a case of HIV-associated acquired EDV with preexisting lesions that were spread along the distribution of the patient’s tattoo, suggesting potential autoinoculation. In individuals living with HIV, the cutaneous features of EDV are not associated with immune status.¹⁴

Acquired EDV also may be associated with other conditions including renal transplantation, IgM deficiency, severe combined immunodeficiency, common variable immunodeficiency, systemic lupus erythematosus, and myasthenia gravis.² Hematologic malignancies such as Hodgkin disease,⁴ natural killer/T-cell lymphoma,⁵ cutaneous T-cell lymphoma,⁶ adult T-cell leukemia,⁷ intestinal diffuse large B-cell lymphoma,^8,9 transformed acute myelogenous lymphoma,¹⁰ and chronic myelogenous leukemia¹¹ also may be associated with EDV. In the inherited form, integral membrane proteins of the endoplasmic reticulum encoded by the genes EVER1 and EVER2 on chromosome 17 are thought to act as restriction factors for certain types of HPV.^2,3 Inactivating mutations in EVER1 and EVER2 result in defects in cell-mediated immunity, rendering patients susceptible to both benign and oncogenic verrucous infections.^2,3 Currently, it is believed that immunosuppressed states may result in defects in cell-mediated immunity that make patients similarly susceptible to these virulent strains of HPV, resulting in an acquired form of EDV.³ Interestingly, the clinical and histologic presentation is identical for acquired EDV and genetic EDV.

Due to the general resistance of EDV to treatment, a variety of options for acquired EDV have been explored including topical and systemic retinoids, cryotherapy, interferon alfa‐2a, zidovudine, ketoconazole, corticosteroids, podophyllotoxin, imiquimod, cidofovir, electrosurgery, 5‐fluorouracil, glycolic acid, temporized diathermy, and methyl aminolevulinate photodynamic therapy.³ Highly active antiretroviral therapy has been proposed as a potential treatment modality for HIV-associated cases; however, acquired EDV has been reported to develop as an immune reconstitution inflammatory syndrome after the initiation of highly active antiretroviral therapy.¹⁵

Combination therapy consisting of a systemic retinoid, immunotherapy, and cryotherapy was initiated for our patient. Human papillomavirus infection is marked by epithelial hyperplasia, and retinoids induce antiproliferation through the control of epithelial cell differentiation.¹⁶ The specific mechanism of action of retinoids in EDV treatment is unknown; however, the beneficial effects may result from the modification of terminal differentiation, a direct antiviral action, or the enhancement of killer T cells.¹⁷ Immunotherapy with C albicans antigen initiates an inflammatory reaction that leads to an immune response directed against the virus, thus reducing the number of warts.² Cryotherapy aims to destroy the lesion but not the virus.² The combination of systemic retinoids, immunotherapy, and destruction may target EDV via multiple potentially synergistic mechanisms. Thus, a multimodal approach can be beneficial in patients with recalcitrant acquired EDV.

The occurrence of EDV is rare, and data on treatment are limited in number resulting in general uncertainty about the efficacy of therapies. Elucidation of the specific mechanism of immunosuppression and its effects on T lymphocytes in acquired EDV may shed light on the most effective treatments. We present this novel case of a patient with HIV-associated acquired EDV who responded favorably to a combination treatment of acitretin, intralesional C albicans antigen, and cryotherapy.

To the Editor:

Epidermodysplasia verruciformis (EDV) is a rare generalized form of epidermal dysplasia that is linked to certain subtypes of human papillomavirus (HPV) infection and inherited or acquired states of immunodeficiency.^1-3 The inherited form most commonly manifests via autosomal-recessive inactivation of the EVER1 and EVER2 genes that encode integral membrane proteins in the endoplasmic reticulum, though cases of autosomal-dominant and X-linked inheritance have been reported.^1-3 Acquired cases have been reported in patients lacking immunocompetency, including transplant recipients and patients living with HIV.^4-11 We present the case of a patient with HIV-associated EDV who was treated successfully with intralesional Candida albicans antigen, oral acitretin, and cryotherapy.

A 56-year-old man presented for evaluation of several cutaneous lesions that had developed over several months on the neck and over many years on the hands and feet. He had a 16-year history of HIV, Castleman disease, and primary effusion lymphoma in remission that was treated with rituximab, etoposide phosphate, prednisone, vincristine sulfate, cyclophosphamide, and doxorubicin hydrochloride 10 or more years ago. The patient denied pruritus or pain associated with the skin lesions. He was intermittently taking immunosuppressants and antiretrovirals including dolutegravir and emtricitabine-tenofovir for 3 years. Prior treatments of the lesions included cryotherapy and over-the-counter 17% salicylic acid. Physical examination revealed the presence of innumerable, clustered, verrucous, scaly papules on the dorsal and palmoplantar regions of the hands (Figure 1), as well as hypopigmented macules clustered on the neck that morphologically resembled tinea versicolor (Figure 2). The physical examination was otherwise unremarkable.

Complete blood cell counts as well as lipid, liver, and renal function panel results were unremarkable. Laboratory examination also revealed a CD4 cell count of 373/µL (reference range, 320–1900/µL) and an undetectable HIV copy number (<40 copies/mL). A punch biopsy of a hypopigmented macule on the left side of the neck revealed epidermal acanthosis, hypergranulosis, and hyperkeratosis, with blue-gray cytoplasm observed in the keratinocytes (Figure 3). Koilocytes with perinuclear clearing associated with keratinocytes in the upper epidermis were noted. Based on the clinical and histopathologic correlation, acquired EDV was diagnosed.

Given that HIV-associated EDV often is recalcitrant and there is a lack of consistent and effective treatment, the patient initially was prescribed oral acitretin 25 mg/d with intralesional C albicans antigen injected once per month into the lesions along with concurrent cryotherapy. At subsequent monthly follow-ups, the involved areas were notably thinner and flat. The patient reported no remarkable side effects from the systemic retinoid treatment such as abdominal pain, photosensitivity, or headaches, though he did experience mild xerosis. Complete resolution of EDV occurred with multimodal therapy—acitretin, cryotherapy, and intralesional Candida antigen. Palmar verrucae were much improved, and he is currently continuing therapy.

Epidermodysplasia verruciformis is a rare genodermatosis associated with an abnormal susceptibility to cutaneous HPV and can be acquired in immunocompromised patients. Patients with EDV present with a clinically heterogeneous disease that can manifest as hypopigmented, red-brown macules with scaling on the trunk, neck, and extremities, which are morphologically similar to tinea versicolor, or patients can present with flat wartlike papules that are most commonly found on the face, hands, and feet.^2,3 Epidermodysplasia verruciformis can be distinguished from EDV-like eruptions and other generalized verrucoses by its characteristic histologic appearance and by the demonstration of HPV within the lesions, typically subtypes HPV-5 and HPV-8.^1-3 Classic EDV histopathologic findings include mild to moderate acanthosis and hyperkeratosis with enlarged keratinocytes featuring blue-gray cytoplasm and perinuclear halos.¹

The histologic differential diagnosis of EDV is quite broad and includes common verrucae, which may be distinguished by the absence of blue-gray discoloration of the cytoplasm among the individual keratinocytes.¹ Verruca plana and condylomata also may mimic EDV, and patients may present with minimal papillomatosis of the surface epidermis.² Squamous cell carcinoma in situ (SCC-IS) and particularly bowenoid papulosis also may share similar histologic features.² However, in SCC-IS, there typically is full-thickness dysplasia of the epidermis, which is not present in EDV. Nonetheless, EDV is equivalent to SCC-IS in its clinical behavior. Bowenoid papulosis shares similar findings, but lesions generally are located in the genital areas and linked to HPV-16 and HPV-18.² Additional histologic features of EDV have been described in the entity of EDV acanthoma, specifically incidental findings present in association with other cutaneous neoplasms including acantholytic acanthomas, condylomas, intradermal nevi, and seborrheic keratoses.¹²

The pathophysiology of EDV is thought to be specifically associated with patients with immunocompromised conditions. Particular attention has been paid to the association between EDV and HIV. Anselmo et al¹³ reported a case of HIV-associated acquired EDV with preexisting lesions that were spread along the distribution of the patient’s tattoo, suggesting potential autoinoculation. In individuals living with HIV, the cutaneous features of EDV are not associated with immune status.¹⁴

Acquired EDV also may be associated with other conditions including renal transplantation, IgM deficiency, severe combined immunodeficiency, common variable immunodeficiency, systemic lupus erythematosus, and myasthenia gravis.² Hematologic malignancies such as Hodgkin disease,⁴ natural killer/T-cell lymphoma,⁵ cutaneous T-cell lymphoma,⁶ adult T-cell leukemia,⁷ intestinal diffuse large B-cell lymphoma,^8,9 transformed acute myelogenous lymphoma,¹⁰ and chronic myelogenous leukemia¹¹ also may be associated with EDV. In the inherited form, integral membrane proteins of the endoplasmic reticulum encoded by the genes EVER1 and EVER2 on chromosome 17 are thought to act as restriction factors for certain types of HPV.^2,3 Inactivating mutations in EVER1 and EVER2 result in defects in cell-mediated immunity, rendering patients susceptible to both benign and oncogenic verrucous infections.^2,3 Currently, it is believed that immunosuppressed states may result in defects in cell-mediated immunity that make patients similarly susceptible to these virulent strains of HPV, resulting in an acquired form of EDV.³ Interestingly, the clinical and histologic presentation is identical for acquired EDV and genetic EDV.

Due to the general resistance of EDV to treatment, a variety of options for acquired EDV have been explored including topical and systemic retinoids, cryotherapy, interferon alfa‐2a, zidovudine, ketoconazole, corticosteroids, podophyllotoxin, imiquimod, cidofovir, electrosurgery, 5‐fluorouracil, glycolic acid, temporized diathermy, and methyl aminolevulinate photodynamic therapy.³ Highly active antiretroviral therapy has been proposed as a potential treatment modality for HIV-associated cases; however, acquired EDV has been reported to develop as an immune reconstitution inflammatory syndrome after the initiation of highly active antiretroviral therapy.¹⁵

Combination therapy consisting of a systemic retinoid, immunotherapy, and cryotherapy was initiated for our patient. Human papillomavirus infection is marked by epithelial hyperplasia, and retinoids induce antiproliferation through the control of epithelial cell differentiation.¹⁶ The specific mechanism of action of retinoids in EDV treatment is unknown; however, the beneficial effects may result from the modification of terminal differentiation, a direct antiviral action, or the enhancement of killer T cells.¹⁷ Immunotherapy with C albicans antigen initiates an inflammatory reaction that leads to an immune response directed against the virus, thus reducing the number of warts.² Cryotherapy aims to destroy the lesion but not the virus.² The combination of systemic retinoids, immunotherapy, and destruction may target EDV via multiple potentially synergistic mechanisms. Thus, a multimodal approach can be beneficial in patients with recalcitrant acquired EDV.

The occurrence of EDV is rare, and data on treatment are limited in number resulting in general uncertainty about the efficacy of therapies. Elucidation of the specific mechanism of immunosuppression and its effects on T lymphocytes in acquired EDV may shed light on the most effective treatments. We present this novel case of a patient with HIV-associated acquired EDV who responded favorably to a combination treatment of acitretin, intralesional C albicans antigen, and cryotherapy.

To the Editor:

Epidermodysplasia verruciformis (EDV) is a rare generalized form of epidermal dysplasia that is linked to certain subtypes of human papillomavirus (HPV) infection and inherited or acquired states of immunodeficiency.^1-3 The inherited form most commonly manifests via autosomal-recessive inactivation of the EVER1 and EVER2 genes that encode integral membrane proteins in the endoplasmic reticulum, though cases of autosomal-dominant and X-linked inheritance have been reported.^1-3 Acquired cases have been reported in patients lacking immunocompetency, including transplant recipients and patients living with HIV.^4-11 We present the case of a patient with HIV-associated EDV who was treated successfully with intralesional Candida albicans antigen, oral acitretin, and cryotherapy.

A 56-year-old man presented for evaluation of several cutaneous lesions that had developed over several months on the neck and over many years on the hands and feet. He had a 16-year history of HIV, Castleman disease, and primary effusion lymphoma in remission that was treated with rituximab, etoposide phosphate, prednisone, vincristine sulfate, cyclophosphamide, and doxorubicin hydrochloride 10 or more years ago. The patient denied pruritus or pain associated with the skin lesions. He was intermittently taking immunosuppressants and antiretrovirals including dolutegravir and emtricitabine-tenofovir for 3 years. Prior treatments of the lesions included cryotherapy and over-the-counter 17% salicylic acid. Physical examination revealed the presence of innumerable, clustered, verrucous, scaly papules on the dorsal and palmoplantar regions of the hands (Figure 1), as well as hypopigmented macules clustered on the neck that morphologically resembled tinea versicolor (Figure 2). The physical examination was otherwise unremarkable.

Complete blood cell counts as well as lipid, liver, and renal function panel results were unremarkable. Laboratory examination also revealed a CD4 cell count of 373/µL (reference range, 320–1900/µL) and an undetectable HIV copy number (<40 copies/mL). A punch biopsy of a hypopigmented macule on the left side of the neck revealed epidermal acanthosis, hypergranulosis, and hyperkeratosis, with blue-gray cytoplasm observed in the keratinocytes (Figure 3). Koilocytes with perinuclear clearing associated with keratinocytes in the upper epidermis were noted. Based on the clinical and histopathologic correlation, acquired EDV was diagnosed.

Given that HIV-associated EDV often is recalcitrant and there is a lack of consistent and effective treatment, the patient initially was prescribed oral acitretin 25 mg/d with intralesional C albicans antigen injected once per month into the lesions along with concurrent cryotherapy. At subsequent monthly follow-ups, the involved areas were notably thinner and flat. The patient reported no remarkable side effects from the systemic retinoid treatment such as abdominal pain, photosensitivity, or headaches, though he did experience mild xerosis. Complete resolution of EDV occurred with multimodal therapy—acitretin, cryotherapy, and intralesional Candida antigen. Palmar verrucae were much improved, and he is currently continuing therapy.

Epidermodysplasia verruciformis is a rare genodermatosis associated with an abnormal susceptibility to cutaneous HPV and can be acquired in immunocompromised patients. Patients with EDV present with a clinically heterogeneous disease that can manifest as hypopigmented, red-brown macules with scaling on the trunk, neck, and extremities, which are morphologically similar to tinea versicolor, or patients can present with flat wartlike papules that are most commonly found on the face, hands, and feet.^2,3 Epidermodysplasia verruciformis can be distinguished from EDV-like eruptions and other generalized verrucoses by its characteristic histologic appearance and by the demonstration of HPV within the lesions, typically subtypes HPV-5 and HPV-8.^1-3 Classic EDV histopathologic findings include mild to moderate acanthosis and hyperkeratosis with enlarged keratinocytes featuring blue-gray cytoplasm and perinuclear halos.¹

The histologic differential diagnosis of EDV is quite broad and includes common verrucae, which may be distinguished by the absence of blue-gray discoloration of the cytoplasm among the individual keratinocytes.¹ Verruca plana and condylomata also may mimic EDV, and patients may present with minimal papillomatosis of the surface epidermis.² Squamous cell carcinoma in situ (SCC-IS) and particularly bowenoid papulosis also may share similar histologic features.² However, in SCC-IS, there typically is full-thickness dysplasia of the epidermis, which is not present in EDV. Nonetheless, EDV is equivalent to SCC-IS in its clinical behavior. Bowenoid papulosis shares similar findings, but lesions generally are located in the genital areas and linked to HPV-16 and HPV-18.² Additional histologic features of EDV have been described in the entity of EDV acanthoma, specifically incidental findings present in association with other cutaneous neoplasms including acantholytic acanthomas, condylomas, intradermal nevi, and seborrheic keratoses.¹²

The pathophysiology of EDV is thought to be specifically associated with patients with immunocompromised conditions. Particular attention has been paid to the association between EDV and HIV. Anselmo et al¹³ reported a case of HIV-associated acquired EDV with preexisting lesions that were spread along the distribution of the patient’s tattoo, suggesting potential autoinoculation. In individuals living with HIV, the cutaneous features of EDV are not associated with immune status.¹⁴

Acquired EDV also may be associated with other conditions including renal transplantation, IgM deficiency, severe combined immunodeficiency, common variable immunodeficiency, systemic lupus erythematosus, and myasthenia gravis.² Hematologic malignancies such as Hodgkin disease,⁴ natural killer/T-cell lymphoma,⁵ cutaneous T-cell lymphoma,⁶ adult T-cell leukemia,⁷ intestinal diffuse large B-cell lymphoma,^8,9 transformed acute myelogenous lymphoma,¹⁰ and chronic myelogenous leukemia¹¹ also may be associated with EDV. In the inherited form, integral membrane proteins of the endoplasmic reticulum encoded by the genes EVER1 and EVER2 on chromosome 17 are thought to act as restriction factors for certain types of HPV.^2,3 Inactivating mutations in EVER1 and EVER2 result in defects in cell-mediated immunity, rendering patients susceptible to both benign and oncogenic verrucous infections.^2,3 Currently, it is believed that immunosuppressed states may result in defects in cell-mediated immunity that make patients similarly susceptible to these virulent strains of HPV, resulting in an acquired form of EDV.³ Interestingly, the clinical and histologic presentation is identical for acquired EDV and genetic EDV.

Due to the general resistance of EDV to treatment, a variety of options for acquired EDV have been explored including topical and systemic retinoids, cryotherapy, interferon alfa‐2a, zidovudine, ketoconazole, corticosteroids, podophyllotoxin, imiquimod, cidofovir, electrosurgery, 5‐fluorouracil, glycolic acid, temporized diathermy, and methyl aminolevulinate photodynamic therapy.³ Highly active antiretroviral therapy has been proposed as a potential treatment modality for HIV-associated cases; however, acquired EDV has been reported to develop as an immune reconstitution inflammatory syndrome after the initiation of highly active antiretroviral therapy.¹⁵

Combination therapy consisting of a systemic retinoid, immunotherapy, and cryotherapy was initiated for our patient. Human papillomavirus infection is marked by epithelial hyperplasia, and retinoids induce antiproliferation through the control of epithelial cell differentiation.¹⁶ The specific mechanism of action of retinoids in EDV treatment is unknown; however, the beneficial effects may result from the modification of terminal differentiation, a direct antiviral action, or the enhancement of killer T cells.¹⁷ Immunotherapy with C albicans antigen initiates an inflammatory reaction that leads to an immune response directed against the virus, thus reducing the number of warts.² Cryotherapy aims to destroy the lesion but not the virus.² The combination of systemic retinoids, immunotherapy, and destruction may target EDV via multiple potentially synergistic mechanisms. Thus, a multimodal approach can be beneficial in patients with recalcitrant acquired EDV.

The occurrence of EDV is rare, and data on treatment are limited in number resulting in general uncertainty about the efficacy of therapies. Elucidation of the specific mechanism of immunosuppression and its effects on T lymphocytes in acquired EDV may shed light on the most effective treatments. We present this novel case of a patient with HIV-associated acquired EDV who responded favorably to a combination treatment of acitretin, intralesional C albicans antigen, and cryotherapy.

Migraine is the single most common neurologic condition worldwide and is particularly predominant among women during their reproductive years. There are many important questions that arise when women with migraine start pregnancy planning, most of which involve acute and preventive medication use and red flags for headache in pregnancy. As of yet, there have been no large-scale epidemiologic studies looking at pregnancy risks for people with migraine. Specifically, if migraine is a statistically significant vascular risk factor, does it incur additional risks in pregnancy, which is a prothrombotic state?

Purdue-Smithe and colleagues reviewed a large longitudinal study, the Nurses' Health Study II, a biennial questionnaire that took place from 1989 to 2009 and in which the questions changed yearly. Migraine was assessed on the basis of whether the participants had been given a diagnosis of migraine (or migraine with aura) by a medical professional; outcomes of pregnancy were also determined on the basis of participants providing a comprehensive reproductive history, including pregnancy outcome, gestation length, birth weight, and pregnancy complications.

A total of 2234 participants were included in this study; 1989 of them reported a history of physician-diagnosed migraine, with 1078 classified as having migraine with aura and 1156 classified as having migraine without aura. Adverse pregnancy outcomes more frequently affect multiple gestations; a sensitivity analysis was conducted to restrict the data here to singleton pregnancies. Individuals with migraine were more likely to report a history of infertility, obesity, and oral contraceptive use than were those without migraine. A history of migraine was associated with greater risks for preterm delivery, gestational hypertension, and preeclampsia; however, it was not associated with gestational diabetes or low birth weight. Theses outcomes were independent of age during pregnancy.

This wide-ranging study does allow us to better discuss potential risks for our patients with migraine. In addition to discussions about estrogen contraception use and stroke risk, it is worth taking a minute to discuss potential pregnancy risks that are more associated with migraine. This will allow our patients to be better aligned with their obstetricians, who can determine if other factors may further elevate these risks. Highlighting areas of risk can allow for better recognition of these potential negative outcomes much earlier.

There is a well-known association between calcitonin gene related peptide (CGRP) and migraine, but what is less understood is how CGRP affects specific features of migraine. CGRP is found in the gut and is therefore thought to have an association with migraine-related nausea, but other migraine associated symptoms, such as photophobia, are less well understood. Schiano di Cola and colleagues sought to determine the effectiveness of galcanezumab specifically in regard to ictal photophobia pain.

They enrolled 80 patients with either high-frequency episodic migraine or chronic migraine who were taking galcanezumab; 47 were included as expressing photophobia as a significant migraine-associated symptom at baseline. The patients were evaluated after 3 months and again after 6 months of treatment. They were asked to record headache days, migraine days, consumption of acute medication, and pain intensity. Migraine Disability Assessment (MIDAS) and Headache Impact Test (HIT-6) scores were also followed up. Improvement with photophobia was determined as either no improvement, slight improvement, moderate improvement, or high improvement. After 3 months of treatment, 68% of patients reported a significant improvement in ictal photophobia, 11 patients reported moderate improvement, and six patients a slight improvement. Two patients reported improvement only after 6 months of treatment.

Post hoc analysis revealed photophobia improvement was not statistically significant in patients who are considered responders to galcanezumab compared with nonresponders. Photophobia improvement was most apparent in patients who were considered triptan responders. It was also more common in people with high-frequency episodic migraine rather than in those with chronic migraine. Migraine disability scores were noted to be higher in participants who did not notice photophobia improvement.

This study highlights the necessity to focus on factors beyond simply migraine frequency and severity. Many of the most disabling characteristics of migraine may not be related to pain directly. More research is currently being undertaken regarding the mechanisms that underlie photophobia in migraine. Ultimately, this will lead to more focused treatment for patients who may have other disabling symptoms associated with their headache disorder.

So much has already been written regarding the association between migraine and vascular risk factors. Migraine is considered a statistically significant risk factor for stroke specifically; migraine with aura has been noted to have a stronger association. Acarsoy and colleagues longitudinally examined the risk for stroke for any cause as it relates to migraine in both middle-aged and older populations.

This prospective population-based trial was embedded in a large Netherlands-based study among middle-aged and older community residents of Rotterdam. A total of 7266 participants were interviewed; 6925 participants had both migraine and stroke information available. Migraine was assessed with a questionnaire based on The International Classification of Headache Disorders (ICHD) criteria. Stroke status was assessed based on World Health Organization criteria and verified from medical records. Participants in this study were continuously monitored for incident stroke through an automatic linking of the study database to national health database files.

Other risk factors selected were body mass index (BMI), smoking history, education level, and physical activity, as well as any history of coronary artery disease, hypertension, or hypercholesterolemia. The average age of the study population was 65.7 years. Among participants with migraine, 20% had a history of migraine with aura. Among all stroke events, 84% were ischemic, and 11% were hemorrhagic. There was no significant difference in stroke-free survival probability between people with and without migraine. Although there was an association between migraine and stroke risk in middle and older ages, this was not statistically significant.

This study highlights, the appropriateness of educating migraine patients in regard to stroke risk. Specifically, patients should not be overly concerned regarding their migraine history. However, this study suggests that there does remain an association, but that this still remains somewhat unclear and less statistically significant in relation to age. When weighing vascular risk factors, more appropriate risks, such as elevated BMI, smoking history, hypertension, and the like should be highlighted, much more so than a history of migraine.

Migraine is the single most common neurologic condition worldwide and is particularly predominant among women during their reproductive years. There are many important questions that arise when women with migraine start pregnancy planning, most of which involve acute and preventive medication use and red flags for headache in pregnancy. As of yet, there have been no large-scale epidemiologic studies looking at pregnancy risks for people with migraine. Specifically, if migraine is a statistically significant vascular risk factor, does it incur additional risks in pregnancy, which is a prothrombotic state?

Purdue-Smithe and colleagues reviewed a large longitudinal study, the Nurses' Health Study II, a biennial questionnaire that took place from 1989 to 2009 and in which the questions changed yearly. Migraine was assessed on the basis of whether the participants had been given a diagnosis of migraine (or migraine with aura) by a medical professional; outcomes of pregnancy were also determined on the basis of participants providing a comprehensive reproductive history, including pregnancy outcome, gestation length, birth weight, and pregnancy complications.

A total of 2234 participants were included in this study; 1989 of them reported a history of physician-diagnosed migraine, with 1078 classified as having migraine with aura and 1156 classified as having migraine without aura. Adverse pregnancy outcomes more frequently affect multiple gestations; a sensitivity analysis was conducted to restrict the data here to singleton pregnancies. Individuals with migraine were more likely to report a history of infertility, obesity, and oral contraceptive use than were those without migraine. A history of migraine was associated with greater risks for preterm delivery, gestational hypertension, and preeclampsia; however, it was not associated with gestational diabetes or low birth weight. Theses outcomes were independent of age during pregnancy.

This wide-ranging study does allow us to better discuss potential risks for our patients with migraine. In addition to discussions about estrogen contraception use and stroke risk, it is worth taking a minute to discuss potential pregnancy risks that are more associated with migraine. This will allow our patients to be better aligned with their obstetricians, who can determine if other factors may further elevate these risks. Highlighting areas of risk can allow for better recognition of these potential negative outcomes much earlier.

There is a well-known association between calcitonin gene related peptide (CGRP) and migraine, but what is less understood is how CGRP affects specific features of migraine. CGRP is found in the gut and is therefore thought to have an association with migraine-related nausea, but other migraine associated symptoms, such as photophobia, are less well understood. Schiano di Cola and colleagues sought to determine the effectiveness of galcanezumab specifically in regard to ictal photophobia pain.

They enrolled 80 patients with either high-frequency episodic migraine or chronic migraine who were taking galcanezumab; 47 were included as expressing photophobia as a significant migraine-associated symptom at baseline. The patients were evaluated after 3 months and again after 6 months of treatment. They were asked to record headache days, migraine days, consumption of acute medication, and pain intensity. Migraine Disability Assessment (MIDAS) and Headache Impact Test (HIT-6) scores were also followed up. Improvement with photophobia was determined as either no improvement, slight improvement, moderate improvement, or high improvement. After 3 months of treatment, 68% of patients reported a significant improvement in ictal photophobia, 11 patients reported moderate improvement, and six patients a slight improvement. Two patients reported improvement only after 6 months of treatment.

Post hoc analysis revealed photophobia improvement was not statistically significant in patients who are considered responders to galcanezumab compared with nonresponders. Photophobia improvement was most apparent in patients who were considered triptan responders. It was also more common in people with high-frequency episodic migraine rather than in those with chronic migraine. Migraine disability scores were noted to be higher in participants who did not notice photophobia improvement.

This study highlights the necessity to focus on factors beyond simply migraine frequency and severity. Many of the most disabling characteristics of migraine may not be related to pain directly. More research is currently being undertaken regarding the mechanisms that underlie photophobia in migraine. Ultimately, this will lead to more focused treatment for patients who may have other disabling symptoms associated with their headache disorder.

So much has already been written regarding the association between migraine and vascular risk factors. Migraine is considered a statistically significant risk factor for stroke specifically; migraine with aura has been noted to have a stronger association. Acarsoy and colleagues longitudinally examined the risk for stroke for any cause as it relates to migraine in both middle-aged and older populations.

This prospective population-based trial was embedded in a large Netherlands-based study among middle-aged and older community residents of Rotterdam. A total of 7266 participants were interviewed; 6925 participants had both migraine and stroke information available. Migraine was assessed with a questionnaire based on The International Classification of Headache Disorders (ICHD) criteria. Stroke status was assessed based on World Health Organization criteria and verified from medical records. Participants in this study were continuously monitored for incident stroke through an automatic linking of the study database to national health database files.

Other risk factors selected were body mass index (BMI), smoking history, education level, and physical activity, as well as any history of coronary artery disease, hypertension, or hypercholesterolemia. The average age of the study population was 65.7 years. Among participants with migraine, 20% had a history of migraine with aura. Among all stroke events, 84% were ischemic, and 11% were hemorrhagic. There was no significant difference in stroke-free survival probability between people with and without migraine. Although there was an association between migraine and stroke risk in middle and older ages, this was not statistically significant.

This study highlights, the appropriateness of educating migraine patients in regard to stroke risk. Specifically, patients should not be overly concerned regarding their migraine history. However, this study suggests that there does remain an association, but that this still remains somewhat unclear and less statistically significant in relation to age. When weighing vascular risk factors, more appropriate risks, such as elevated BMI, smoking history, hypertension, and the like should be highlighted, much more so than a history of migraine.

Migraine is the single most common neurologic condition worldwide and is particularly predominant among women during their reproductive years. There are many important questions that arise when women with migraine start pregnancy planning, most of which involve acute and preventive medication use and red flags for headache in pregnancy. As of yet, there have been no large-scale epidemiologic studies looking at pregnancy risks for people with migraine. Specifically, if migraine is a statistically significant vascular risk factor, does it incur additional risks in pregnancy, which is a prothrombotic state?

Purdue-Smithe and colleagues reviewed a large longitudinal study, the Nurses' Health Study II, a biennial questionnaire that took place from 1989 to 2009 and in which the questions changed yearly. Migraine was assessed on the basis of whether the participants had been given a diagnosis of migraine (or migraine with aura) by a medical professional; outcomes of pregnancy were also determined on the basis of participants providing a comprehensive reproductive history, including pregnancy outcome, gestation length, birth weight, and pregnancy complications.

A total of 2234 participants were included in this study; 1989 of them reported a history of physician-diagnosed migraine, with 1078 classified as having migraine with aura and 1156 classified as having migraine without aura. Adverse pregnancy outcomes more frequently affect multiple gestations; a sensitivity analysis was conducted to restrict the data here to singleton pregnancies. Individuals with migraine were more likely to report a history of infertility, obesity, and oral contraceptive use than were those without migraine. A history of migraine was associated with greater risks for preterm delivery, gestational hypertension, and preeclampsia; however, it was not associated with gestational diabetes or low birth weight. Theses outcomes were independent of age during pregnancy.

This wide-ranging study does allow us to better discuss potential risks for our patients with migraine. In addition to discussions about estrogen contraception use and stroke risk, it is worth taking a minute to discuss potential pregnancy risks that are more associated with migraine. This will allow our patients to be better aligned with their obstetricians, who can determine if other factors may further elevate these risks. Highlighting areas of risk can allow for better recognition of these potential negative outcomes much earlier.

There is a well-known association between calcitonin gene related peptide (CGRP) and migraine, but what is less understood is how CGRP affects specific features of migraine. CGRP is found in the gut and is therefore thought to have an association with migraine-related nausea, but other migraine associated symptoms, such as photophobia, are less well understood. Schiano di Cola and colleagues sought to determine the effectiveness of galcanezumab specifically in regard to ictal photophobia pain.

They enrolled 80 patients with either high-frequency episodic migraine or chronic migraine who were taking galcanezumab; 47 were included as expressing photophobia as a significant migraine-associated symptom at baseline. The patients were evaluated after 3 months and again after 6 months of treatment. They were asked to record headache days, migraine days, consumption of acute medication, and pain intensity. Migraine Disability Assessment (MIDAS) and Headache Impact Test (HIT-6) scores were also followed up. Improvement with photophobia was determined as either no improvement, slight improvement, moderate improvement, or high improvement. After 3 months of treatment, 68% of patients reported a significant improvement in ictal photophobia, 11 patients reported moderate improvement, and six patients a slight improvement. Two patients reported improvement only after 6 months of treatment.

Post hoc analysis revealed photophobia improvement was not statistically significant in patients who are considered responders to galcanezumab compared with nonresponders. Photophobia improvement was most apparent in patients who were considered triptan responders. It was also more common in people with high-frequency episodic migraine rather than in those with chronic migraine. Migraine disability scores were noted to be higher in participants who did not notice photophobia improvement.

This study highlights the necessity to focus on factors beyond simply migraine frequency and severity. Many of the most disabling characteristics of migraine may not be related to pain directly. More research is currently being undertaken regarding the mechanisms that underlie photophobia in migraine. Ultimately, this will lead to more focused treatment for patients who may have other disabling symptoms associated with their headache disorder.

So much has already been written regarding the association between migraine and vascular risk factors. Migraine is considered a statistically significant risk factor for stroke specifically; migraine with aura has been noted to have a stronger association. Acarsoy and colleagues longitudinally examined the risk for stroke for any cause as it relates to migraine in both middle-aged and older populations.

This prospective population-based trial was embedded in a large Netherlands-based study among middle-aged and older community residents of Rotterdam. A total of 7266 participants were interviewed; 6925 participants had both migraine and stroke information available. Migraine was assessed with a questionnaire based on The International Classification of Headache Disorders (ICHD) criteria. Stroke status was assessed based on World Health Organization criteria and verified from medical records. Participants in this study were continuously monitored for incident stroke through an automatic linking of the study database to national health database files.

Other risk factors selected were body mass index (BMI), smoking history, education level, and physical activity, as well as any history of coronary artery disease, hypertension, or hypercholesterolemia. The average age of the study population was 65.7 years. Among participants with migraine, 20% had a history of migraine with aura. Among all stroke events, 84% were ischemic, and 11% were hemorrhagic. There was no significant difference in stroke-free survival probability between people with and without migraine. Although there was an association between migraine and stroke risk in middle and older ages, this was not statistically significant.

This study highlights, the appropriateness of educating migraine patients in regard to stroke risk. Specifically, patients should not be overly concerned regarding their migraine history. However, this study suggests that there does remain an association, but that this still remains somewhat unclear and less statistically significant in relation to age. When weighing vascular risk factors, more appropriate risks, such as elevated BMI, smoking history, hypertension, and the like should be highlighted, much more so than a history of migraine.

Two recent studies examined interstitial lung disease (ILD) in patients with rheumatoid arthritis (RA). Albrecht and colleagues examined the prevalence of ILD in German patients with RA using a nationwide claims database from 2007 to 2020. Using diagnosis codes for seropositive and seronegative RA (along with disease-modifying antirheumatic drug prescriptions) as well as ILD, they found the prevalence of ILD to be relatively stable from 1.6% to 2.2%, and that incidence was stable (reported as 0.13%-0.21% per year, rather than per patient-year) over the course of the study. There is likely some misclassification with the primary reliance on diagnosis codes (of the included patients with RA only 44% were seropositive). They also excluded drug-induced ILD by diagnosis code, which may not be sufficient. Overall, the prevalence of ILD seems on the low end of what might be expected and may reflect a need for earlier evaluation to detect subclinical ILD.

Kronzer and colleagues performed a case-control study of 84 patients with incident RA-ILD compared with 233 patients with RA without ILD to evaluate the risk associated with specific anticitrullinated protein antibodies (ACPA) for the development of ILD. Compared with the clinical risk factors of smoking, disease activity, obesity, and glucocorticoid use, six "fine-specificity" ACPA were better able to predict ILD risk, with immunoglobulin (Ig) A2 to citrullinated histone 4 associated with an odds ratio (OR) of 0.08, and the others (IgA2 to citrullinated histone 2A, IgA2 to native cyclic histone 2A, IgA2 to native histone 2A, IgG to cyclic citrullinated filaggrin, and IgG to native cyclic filaggrin) were associated with OR of 2.5-5.5 for ILD. In combination with clinical characteristics, the authors developed a risk score with 93% specificity for RA-ILD that should be validated in other populations.

Suh and colleagues examined the association of RA with another less well-studied organ complication, end-stage renal disease (ESRD), using a large national insurance database. Once again, the accuracy of diagnosis is not fully clear using International Classification of Diseases, Tenth Edition (ICD-10), codes for classification. Overall, people with RA had a higher risk for ESRD than did people without RA, regardless of sex or smoking status. Because no immediate mechanistic connection between RA and ESRD is evident, it is possible that part of the increased risk is due to medications used in RA treatment, such as nonsteroidal anti-inflammatory drugs, but this hypothesis remains to be tested.

Finally, a footnote to the success of the treat-to-target strategy (T2T) in RA comes in a study by Ramiro and colleagues of the RA-BIODAM cohort, which, along with other studies, has shown the success of T2T in achieving and maintaining long-term clinical remission in RA. The effect of T2T on radiographic progression, however, is less clear. In this study, over 500 patients were followed for 2 years and a comparison between the T2T strategy and radiographic damage was made. The T2T strategy consisted of intensification of treatment if the Disease Activity Score (DAS-44) did not achieve a goal of < 1.6. This was compared with the radiographic damage (based on the change in Sharp-van der Heijde score[SvdH]) over a 6-month period. Overall, the change in progression was not different among patients who were treated with a stricter adherence to T2T (ie, a higher proportion of T2T) compared with those who were not, suggesting that a looser application of T2T will not necessarily cause a worsening of radiographic progression. It is possible, given the intervals of assessment in this study, that a longer follow-up after T2T is necessary to detect progression, or, given that patients were not randomly assigned, patients who were more strictly treated with T2T were already at higher risk for radiographic progression. However, this study is also helpful in understanding how insights from controlled trials may play out in usual clinical practice.

Two recent studies examined interstitial lung disease (ILD) in patients with rheumatoid arthritis (RA). Albrecht and colleagues examined the prevalence of ILD in German patients with RA using a nationwide claims database from 2007 to 2020. Using diagnosis codes for seropositive and seronegative RA (along with disease-modifying antirheumatic drug prescriptions) as well as ILD, they found the prevalence of ILD to be relatively stable from 1.6% to 2.2%, and that incidence was stable (reported as 0.13%-0.21% per year, rather than per patient-year) over the course of the study. There is likely some misclassification with the primary reliance on diagnosis codes (of the included patients with RA only 44% were seropositive). They also excluded drug-induced ILD by diagnosis code, which may not be sufficient. Overall, the prevalence of ILD seems on the low end of what might be expected and may reflect a need for earlier evaluation to detect subclinical ILD.

Kronzer and colleagues performed a case-control study of 84 patients with incident RA-ILD compared with 233 patients with RA without ILD to evaluate the risk associated with specific anticitrullinated protein antibodies (ACPA) for the development of ILD. Compared with the clinical risk factors of smoking, disease activity, obesity, and glucocorticoid use, six "fine-specificity" ACPA were better able to predict ILD risk, with immunoglobulin (Ig) A2 to citrullinated histone 4 associated with an odds ratio (OR) of 0.08, and the others (IgA2 to citrullinated histone 2A, IgA2 to native cyclic histone 2A, IgA2 to native histone 2A, IgG to cyclic citrullinated filaggrin, and IgG to native cyclic filaggrin) were associated with OR of 2.5-5.5 for ILD. In combination with clinical characteristics, the authors developed a risk score with 93% specificity for RA-ILD that should be validated in other populations.

Suh and colleagues examined the association of RA with another less well-studied organ complication, end-stage renal disease (ESRD), using a large national insurance database. Once again, the accuracy of diagnosis is not fully clear using International Classification of Diseases, Tenth Edition (ICD-10), codes for classification. Overall, people with RA had a higher risk for ESRD than did people without RA, regardless of sex or smoking status. Because no immediate mechanistic connection between RA and ESRD is evident, it is possible that part of the increased risk is due to medications used in RA treatment, such as nonsteroidal anti-inflammatory drugs, but this hypothesis remains to be tested.

Finally, a footnote to the success of the treat-to-target strategy (T2T) in RA comes in a study by Ramiro and colleagues of the RA-BIODAM cohort, which, along with other studies, has shown the success of T2T in achieving and maintaining long-term clinical remission in RA. The effect of T2T on radiographic progression, however, is less clear. In this study, over 500 patients were followed for 2 years and a comparison between the T2T strategy and radiographic damage was made. The T2T strategy consisted of intensification of treatment if the Disease Activity Score (DAS-44) did not achieve a goal of < 1.6. This was compared with the radiographic damage (based on the change in Sharp-van der Heijde score[SvdH]) over a 6-month period. Overall, the change in progression was not different among patients who were treated with a stricter adherence to T2T (ie, a higher proportion of T2T) compared with those who were not, suggesting that a looser application of T2T will not necessarily cause a worsening of radiographic progression. It is possible, given the intervals of assessment in this study, that a longer follow-up after T2T is necessary to detect progression, or, given that patients were not randomly assigned, patients who were more strictly treated with T2T were already at higher risk for radiographic progression. However, this study is also helpful in understanding how insights from controlled trials may play out in usual clinical practice.

Two recent studies examined interstitial lung disease (ILD) in patients with rheumatoid arthritis (RA). Albrecht and colleagues examined the prevalence of ILD in German patients with RA using a nationwide claims database from 2007 to 2020. Using diagnosis codes for seropositive and seronegative RA (along with disease-modifying antirheumatic drug prescriptions) as well as ILD, they found the prevalence of ILD to be relatively stable from 1.6% to 2.2%, and that incidence was stable (reported as 0.13%-0.21% per year, rather than per patient-year) over the course of the study. There is likely some misclassification with the primary reliance on diagnosis codes (of the included patients with RA only 44% were seropositive). They also excluded drug-induced ILD by diagnosis code, which may not be sufficient. Overall, the prevalence of ILD seems on the low end of what might be expected and may reflect a need for earlier evaluation to detect subclinical ILD.

Kronzer and colleagues performed a case-control study of 84 patients with incident RA-ILD compared with 233 patients with RA without ILD to evaluate the risk associated with specific anticitrullinated protein antibodies (ACPA) for the development of ILD. Compared with the clinical risk factors of smoking, disease activity, obesity, and glucocorticoid use, six "fine-specificity" ACPA were better able to predict ILD risk, with immunoglobulin (Ig) A2 to citrullinated histone 4 associated with an odds ratio (OR) of 0.08, and the others (IgA2 to citrullinated histone 2A, IgA2 to native cyclic histone 2A, IgA2 to native histone 2A, IgG to cyclic citrullinated filaggrin, and IgG to native cyclic filaggrin) were associated with OR of 2.5-5.5 for ILD. In combination with clinical characteristics, the authors developed a risk score with 93% specificity for RA-ILD that should be validated in other populations.

Suh and colleagues examined the association of RA with another less well-studied organ complication, end-stage renal disease (ESRD), using a large national insurance database. Once again, the accuracy of diagnosis is not fully clear using International Classification of Diseases, Tenth Edition (ICD-10), codes for classification. Overall, people with RA had a higher risk for ESRD than did people without RA, regardless of sex or smoking status. Because no immediate mechanistic connection between RA and ESRD is evident, it is possible that part of the increased risk is due to medications used in RA treatment, such as nonsteroidal anti-inflammatory drugs, but this hypothesis remains to be tested.

Finally, a footnote to the success of the treat-to-target strategy (T2T) in RA comes in a study by Ramiro and colleagues of the RA-BIODAM cohort, which, along with other studies, has shown the success of T2T in achieving and maintaining long-term clinical remission in RA. The effect of T2T on radiographic progression, however, is less clear. In this study, over 500 patients were followed for 2 years and a comparison between the T2T strategy and radiographic damage was made. The T2T strategy consisted of intensification of treatment if the Disease Activity Score (DAS-44) did not achieve a goal of < 1.6. This was compared with the radiographic damage (based on the change in Sharp-van der Heijde score[SvdH]) over a 6-month period. Overall, the change in progression was not different among patients who were treated with a stricter adherence to T2T (ie, a higher proportion of T2T) compared with those who were not, suggesting that a looser application of T2T will not necessarily cause a worsening of radiographic progression. It is possible, given the intervals of assessment in this study, that a longer follow-up after T2T is necessary to detect progression, or, given that patients were not randomly assigned, patients who were more strictly treated with T2T were already at higher risk for radiographic progression. However, this study is also helpful in understanding how insights from controlled trials may play out in usual clinical practice.

One therapy that has transformed the management of this disease is anti-CD19 chimeric antigen receptor (CAR) T-cell therapy. Currently there are three FDA-approved options for patients with relapsed/refractory large B-cell lymphoma (LBCL) who have received at least two prior lines of therapy.^[1-3] More recently, axicabtagene ciloleucel (axi-cel) and lisocabtagene maraleucel (liso-cel) have also been approved for second-line therapy on the basis of results of the ZUMA-7 and TRANSFORM studies, respectively.^[4,5]The primary analysis of the TRANSFORM study, which included patients with primary refractory or early relapse of large B-cell lymphoma, is now available. In this study, 184 patients were randomly assigned to receive liso-cel or three cycles of the standard of care (high-dose chemotherapy and autologous stem cell transplantation). After a 17.5-month median follow-up, the liso-cel vs standard-of-care group had significantly improved median event-free survival (hazard ratio [HR] 0.356; 95% CI 0.243-0.522), median progression-free survival (HR 0.400; P < .0001), and complete response rate (74% vs 43%; P < .0001), along with low rates of grade 3 cytokine release syndrome (1%) and neurologic events (4%). This confirms the role of liso-cel in the second-line setting for high-risk patients.

Another promising treatment approach across lymphoma subtypes, including DLBCL, are CD20/CD3 bispecific monoclonal antibodies. The results of the phase 2 trial of glofitamab for patients with relapsed/refractory DLBCL were published recently. This study included 155 patients with relapsed/refractory DLBCL after at least two prior lines of therapy. Approximately one third of patients had received prior CAR T-cell therapy. Patients were treated for a fixed duration of 12 cycles. At a median follow-up of 12.6 months, 39% (95% CI 32%-48%) and 52% (95% CI 43%-60%) of patients achieved complete and objective responses, respectively. Seventy-eight percent of patients with a complete response continued to be in remission at 12 months. Grade 3 or higher cytokine release syndrome was rare and occurred in less than 5% of patients.

Bispecific antibodies have many advantages, including off-the-shelf access and favorable toxicity profiles. Longer follow-up, however, will be required to determine the durability of response beyond 1 year. As bispecific antibodies become available, many questions will emerge, including how best to sequence with CAR T-cell therapy and whether to combine them with other regimens. Additional studies of bispecific antibodies in combination with chemoimmunotherapy and other treatment approaches are underway.

Additional References

1.         Neelapu SS, Locke FL, Bartlett NL, et al. Axicabtagene ciloleucel CAR T-cell therapy in refractory large B-cell lymphoma. N Engl J Med. 2017;377:2531-2544. Doi:10.1056/NEJMoa1707447

2.         Schuster SJ, Bishop MR, Tam CS, et al. Tisagenlecleucel in adult relapsed or refractory diffuse large B-cell lymphoma. N Engl J Med. 2019;380:45-56. Doi:10.1056/NEJMoa1804980

3.         Abramson JS, Palomba ML, Gordon LI, et al. Lisocabtagene maraleucel for patients with relapsed or refractory large B-cell lymphomas (TRANSCEND NHL 001): A multicentre seamless design study. Lancet. 2020;396:839-852. Doi:10.1016/S0140-6736(20)31366-0

4.         Locke FL, Miklos DB, Jacobson CA, et al. Axicabtagene ciloleucel as second-line therapy for large B-cell lymphoma. N Engl J Med. 2022;386:640-654. Doi:10.1056/NEJMoa2116133

5.         Kamdar M, Solomon SR, Arnason J, et al. Lisocabtagene maraleucel versus standard of care with salvage chemotherapy followed by autologous stem cell transplantation as second-line treatment in patients with relapsed or refractory large B-cell lymphoma (TRANSFORM): Results from an interim analysis of an open-label, randomised, phase 3 trial. Lancet. 2022;399:2294-2308. Doi:10.1016/S0140-6736(22)00662-6

One therapy that has transformed the management of this disease is anti-CD19 chimeric antigen receptor (CAR) T-cell therapy. Currently there are three FDA-approved options for patients with relapsed/refractory large B-cell lymphoma (LBCL) who have received at least two prior lines of therapy.^[1-3] More recently, axicabtagene ciloleucel (axi-cel) and lisocabtagene maraleucel (liso-cel) have also been approved for second-line therapy on the basis of results of the ZUMA-7 and TRANSFORM studies, respectively.^[4,5]The primary analysis of the TRANSFORM study, which included patients with primary refractory or early relapse of large B-cell lymphoma, is now available. In this study, 184 patients were randomly assigned to receive liso-cel or three cycles of the standard of care (high-dose chemotherapy and autologous stem cell transplantation). After a 17.5-month median follow-up, the liso-cel vs standard-of-care group had significantly improved median event-free survival (hazard ratio [HR] 0.356; 95% CI 0.243-0.522), median progression-free survival (HR 0.400; P < .0001), and complete response rate (74% vs 43%; P < .0001), along with low rates of grade 3 cytokine release syndrome (1%) and neurologic events (4%). This confirms the role of liso-cel in the second-line setting for high-risk patients.

Another promising treatment approach across lymphoma subtypes, including DLBCL, are CD20/CD3 bispecific monoclonal antibodies. The results of the phase 2 trial of glofitamab for patients with relapsed/refractory DLBCL were published recently. This study included 155 patients with relapsed/refractory DLBCL after at least two prior lines of therapy. Approximately one third of patients had received prior CAR T-cell therapy. Patients were treated for a fixed duration of 12 cycles. At a median follow-up of 12.6 months, 39% (95% CI 32%-48%) and 52% (95% CI 43%-60%) of patients achieved complete and objective responses, respectively. Seventy-eight percent of patients with a complete response continued to be in remission at 12 months. Grade 3 or higher cytokine release syndrome was rare and occurred in less than 5% of patients.

Bispecific antibodies have many advantages, including off-the-shelf access and favorable toxicity profiles. Longer follow-up, however, will be required to determine the durability of response beyond 1 year. As bispecific antibodies become available, many questions will emerge, including how best to sequence with CAR T-cell therapy and whether to combine them with other regimens. Additional studies of bispecific antibodies in combination with chemoimmunotherapy and other treatment approaches are underway.

Additional References

1.         Neelapu SS, Locke FL, Bartlett NL, et al. Axicabtagene ciloleucel CAR T-cell therapy in refractory large B-cell lymphoma. N Engl J Med. 2017;377:2531-2544. Doi:10.1056/NEJMoa1707447

2.         Schuster SJ, Bishop MR, Tam CS, et al. Tisagenlecleucel in adult relapsed or refractory diffuse large B-cell lymphoma. N Engl J Med. 2019;380:45-56. Doi:10.1056/NEJMoa1804980

3.         Abramson JS, Palomba ML, Gordon LI, et al. Lisocabtagene maraleucel for patients with relapsed or refractory large B-cell lymphomas (TRANSCEND NHL 001): A multicentre seamless design study. Lancet. 2020;396:839-852. Doi:10.1016/S0140-6736(20)31366-0

4.         Locke FL, Miklos DB, Jacobson CA, et al. Axicabtagene ciloleucel as second-line therapy for large B-cell lymphoma. N Engl J Med. 2022;386:640-654. Doi:10.1056/NEJMoa2116133

5.         Kamdar M, Solomon SR, Arnason J, et al. Lisocabtagene maraleucel versus standard of care with salvage chemotherapy followed by autologous stem cell transplantation as second-line treatment in patients with relapsed or refractory large B-cell lymphoma (TRANSFORM): Results from an interim analysis of an open-label, randomised, phase 3 trial. Lancet. 2022;399:2294-2308. Doi:10.1016/S0140-6736(22)00662-6

One therapy that has transformed the management of this disease is anti-CD19 chimeric antigen receptor (CAR) T-cell therapy. Currently there are three FDA-approved options for patients with relapsed/refractory large B-cell lymphoma (LBCL) who have received at least two prior lines of therapy.^[1-3] More recently, axicabtagene ciloleucel (axi-cel) and lisocabtagene maraleucel (liso-cel) have also been approved for second-line therapy on the basis of results of the ZUMA-7 and TRANSFORM studies, respectively.^[4,5]The primary analysis of the TRANSFORM study, which included patients with primary refractory or early relapse of large B-cell lymphoma, is now available. In this study, 184 patients were randomly assigned to receive liso-cel or three cycles of the standard of care (high-dose chemotherapy and autologous stem cell transplantation). After a 17.5-month median follow-up, the liso-cel vs standard-of-care group had significantly improved median event-free survival (hazard ratio [HR] 0.356; 95% CI 0.243-0.522), median progression-free survival (HR 0.400; P < .0001), and complete response rate (74% vs 43%; P < .0001), along with low rates of grade 3 cytokine release syndrome (1%) and neurologic events (4%). This confirms the role of liso-cel in the second-line setting for high-risk patients.

Another promising treatment approach across lymphoma subtypes, including DLBCL, are CD20/CD3 bispecific monoclonal antibodies. The results of the phase 2 trial of glofitamab for patients with relapsed/refractory DLBCL were published recently. This study included 155 patients with relapsed/refractory DLBCL after at least two prior lines of therapy. Approximately one third of patients had received prior CAR T-cell therapy. Patients were treated for a fixed duration of 12 cycles. At a median follow-up of 12.6 months, 39% (95% CI 32%-48%) and 52% (95% CI 43%-60%) of patients achieved complete and objective responses, respectively. Seventy-eight percent of patients with a complete response continued to be in remission at 12 months. Grade 3 or higher cytokine release syndrome was rare and occurred in less than 5% of patients.

Bispecific antibodies have many advantages, including off-the-shelf access and favorable toxicity profiles. Longer follow-up, however, will be required to determine the durability of response beyond 1 year. As bispecific antibodies become available, many questions will emerge, including how best to sequence with CAR T-cell therapy and whether to combine them with other regimens. Additional studies of bispecific antibodies in combination with chemoimmunotherapy and other treatment approaches are underway.

Additional References

1.         Neelapu SS, Locke FL, Bartlett NL, et al. Axicabtagene ciloleucel CAR T-cell therapy in refractory large B-cell lymphoma. N Engl J Med. 2017;377:2531-2544. Doi:10.1056/NEJMoa1707447

2.         Schuster SJ, Bishop MR, Tam CS, et al. Tisagenlecleucel in adult relapsed or refractory diffuse large B-cell lymphoma. N Engl J Med. 2019;380:45-56. Doi:10.1056/NEJMoa1804980

3.         Abramson JS, Palomba ML, Gordon LI, et al. Lisocabtagene maraleucel for patients with relapsed or refractory large B-cell lymphomas (TRANSCEND NHL 001): A multicentre seamless design study. Lancet. 2020;396:839-852. Doi:10.1016/S0140-6736(20)31366-0

4.         Locke FL, Miklos DB, Jacobson CA, et al. Axicabtagene ciloleucel as second-line therapy for large B-cell lymphoma. N Engl J Med. 2022;386:640-654. Doi:10.1056/NEJMoa2116133

5.         Kamdar M, Solomon SR, Arnason J, et al. Lisocabtagene maraleucel versus standard of care with salvage chemotherapy followed by autologous stem cell transplantation as second-line treatment in patients with relapsed or refractory large B-cell lymphoma (TRANSFORM): Results from an interim analysis of an open-label, randomised, phase 3 trial. Lancet. 2022;399:2294-2308. Doi:10.1016/S0140-6736(22)00662-6

A post hoc analysis of the ShortHER trial, including 784 patients with hormone-positive (HR+) and human epidermal growth factor receptor 2–positive (HER2+) early breast cancer who received adjuvant trastuzumab plus chemotherapy, showed that adjuvant endocrine therapy (ET) with an aromatase inhibitor (AI) was associated with better outcomes than tamoxifen (TAM) or TAM and AI (TAM-AI) in this population. Disease-free survival rates at 8 years were 86.4% for AI vs 79.7% for the TAM/TAM-AI groups, with an absolute difference of 6.7% (log-rank P = .013). This effect was seen independently of menopausal status in a multivariate analysis.

In the exploratory analysis focusing on the premenopausal patients, the addition of gonadotropin-releasing hormone to ET was associated with a significantly better disease-free survival. This was also noted in an exploratory subgroup analysis of the SOFT trial,^[1] which showed greater benefit from the addition of ovarian suppression to TAM, as compared with TAM alone, among women with HER2+ disease (hazard ratio 0.41; 95% CI 0.22-0.75).

It is important to note that not all patients in the ShortHER trial received the standard-of-care duration of adjuvant trastuzumab; half of them received only 9-week treatment as opposed to the standard 12 months of adjuvant therapy. It is unclear whether this difference in adjuvant therapy could have affected the results, although the disease-free survival multivariate analysis showed no significant effect of the treatment arm on the role of ET. More studies are needed to verify the optimal adjuvant ET for patients with HR+/HER2+ breast cancer, especially in premenopausal patients.

Contralateral Prophylactic Mastectomy Offers No Survival Advantage in Triple-Negative Breast Cancer

There is insufficient evidence that contralateral prophylactic mastectomy (CPM) improves survival in patients with unilateral triple-negative breast cancer (TNBC). A multi-institutional database study, including 796 patients with TNBC, of which 15.5% underwent CPM, showed that CPM did not offer survival benefit to patients with unilateral TNBC. Women who underwent CPM were more likely to be White (P < .001), younger (P < .001), and had had genetic testing performed (P < .001). While there was a borderline improvement in 5-year unadjusted overall survival for patients undergoing CPM compared with no CPM overall (95.1% vs 85.0%; P = .05), no significant improvement was observed for local recurrence-free survival (P = .40) or distant recurrence-free survival (P = .37). Very few (n = 15/673, 2.2%) of the no-CPM patients developed a new primary breast cancer; 3 of the 15 patients were known BRCA1 or BRCA2 mutation carriers. Among the genetic mutation carriers, 5-year overall survival was 97.2% for CPM vs 84.1% for no CPM (P = .35). This study did not demonstrate any statistically significant survival difference between CPM compared with no CPM, regardless of the presence of a BRCA mutation, although prior studies have shown improved outcomes for CPM in BRCA mutation carriers.^[2] Larger prospective studies are needed to evaluate the potential benefit of CPM among patients with TNBC, especially patients with BRCA1/2 mutations.

Adding Endocrine Therapy to Dual Anti-HER2 Targeted Therapy Beneficial in HER2+/HR+ Metastatic Breast Cancer

The current first-line standard of care for HER2+ metastatic breast cancer is dual anti-HER2 targeted therapy plus chemotherapy, with consideration for maintenance treatment with anti-HER2 therapy and ET for patients with HR+ and HER2+ metastatic breast cancer. The potential benefit of adding ET for patients with HR+/HER2+ metastatic breast cancer has been reported previously, but data overall are limited. This study analyzed the real-world data of 147 patients with HR+/HER2+ metastatic breast cancer from a prospective registry and who received first-line chemotherapy plus trastuzumab and pertuzumab with (n = 91) or without (n = 56) concurrent ET. The findings showed that adding ET resulted in a significant improvement in 5-year progression-free survival (PFS) (hazard ratio 0.59; P = .031) and overall survival (hazard ratio 0.52; P = .018) compared with not adding ET. No new safety concerns were identified when combining HER2+ targeted therapy and ET. While this is a small retrospective analysis, results are certainly encouraging and support the addition of ET to dual anti-HER2 therapy as maintenance therapy post chemotherapy in this subset of patients.

High PD-L2 Levels May Predict Worse Clinical Outcomes in ER+ Breast Cancer

Programmed cell death-1 ligand-2 (PD-L2) is a second ligand for programmed cell death-1 (PD-1) and inhibits T-cell activation. A retrospective study including patients with estrogen receptor–positive (ER+) breast cancer looked at PD-L2 protein levels in cancer cells and stromal cells of therapy-naive, locoregional ER+ breast cancer in the main study cohort (n = 684) and in an independent validation cohort (n = 273), and correlated findings with PFS. High levels of PD-L2 protein were present in up to one third (33%) of ER+ tumors and were associated with shorter PFS in the entire cohort of patients with ER+ breast cancer (hazard ratio 2.0; P < .001) and in the subgroup of patients treated with adjuvant chemotherapy (hazard ratio 3.4; P < .001). A multivariable analysis showed that high levels of PD-L2 were an independent prognostic marker in ER+ patients. These findings suggest that high PD-L2 is associated with unfavorable prognosis in ER+ breast cancer and may be a potential biomarker of response to checkpoint inhibitors.

Additional References

1. Francis PA, Pagani O, Fleming GF, et al for the SOFT and TEXT Investigators and the International Breast Cancer Study Group. Tailoring adjuvant endocrine therapy for premenopausal breast cancer. N Engl J Med. 2018;379:122-137. Doi: 10.1056/NEJMoa1803164
2. Li X, You R, Wang X, et al. Effectiveness of prophylactic surgeries in BRCA1 or BRCA2 mutation carriers: A meta-analysis and systematic review. Clin Cancer Res. 2016;22:3971-3981. Doi: 10.1158/1078-0432.CCR-15-1465

A post hoc analysis of the ShortHER trial, including 784 patients with hormone-positive (HR+) and human epidermal growth factor receptor 2–positive (HER2+) early breast cancer who received adjuvant trastuzumab plus chemotherapy, showed that adjuvant endocrine therapy (ET) with an aromatase inhibitor (AI) was associated with better outcomes than tamoxifen (TAM) or TAM and AI (TAM-AI) in this population. Disease-free survival rates at 8 years were 86.4% for AI vs 79.7% for the TAM/TAM-AI groups, with an absolute difference of 6.7% (log-rank P = .013). This effect was seen independently of menopausal status in a multivariate analysis.

In the exploratory analysis focusing on the premenopausal patients, the addition of gonadotropin-releasing hormone to ET was associated with a significantly better disease-free survival. This was also noted in an exploratory subgroup analysis of the SOFT trial,^[1] which showed greater benefit from the addition of ovarian suppression to TAM, as compared with TAM alone, among women with HER2+ disease (hazard ratio 0.41; 95% CI 0.22-0.75).

It is important to note that not all patients in the ShortHER trial received the standard-of-care duration of adjuvant trastuzumab; half of them received only 9-week treatment as opposed to the standard 12 months of adjuvant therapy. It is unclear whether this difference in adjuvant therapy could have affected the results, although the disease-free survival multivariate analysis showed no significant effect of the treatment arm on the role of ET. More studies are needed to verify the optimal adjuvant ET for patients with HR+/HER2+ breast cancer, especially in premenopausal patients.

Contralateral Prophylactic Mastectomy Offers No Survival Advantage in Triple-Negative Breast Cancer

There is insufficient evidence that contralateral prophylactic mastectomy (CPM) improves survival in patients with unilateral triple-negative breast cancer (TNBC). A multi-institutional database study, including 796 patients with TNBC, of which 15.5% underwent CPM, showed that CPM did not offer survival benefit to patients with unilateral TNBC. Women who underwent CPM were more likely to be White (P < .001), younger (P < .001), and had had genetic testing performed (P < .001). While there was a borderline improvement in 5-year unadjusted overall survival for patients undergoing CPM compared with no CPM overall (95.1% vs 85.0%; P = .05), no significant improvement was observed for local recurrence-free survival (P = .40) or distant recurrence-free survival (P = .37). Very few (n = 15/673, 2.2%) of the no-CPM patients developed a new primary breast cancer; 3 of the 15 patients were known BRCA1 or BRCA2 mutation carriers. Among the genetic mutation carriers, 5-year overall survival was 97.2% for CPM vs 84.1% for no CPM (P = .35). This study did not demonstrate any statistically significant survival difference between CPM compared with no CPM, regardless of the presence of a BRCA mutation, although prior studies have shown improved outcomes for CPM in BRCA mutation carriers.^[2] Larger prospective studies are needed to evaluate the potential benefit of CPM among patients with TNBC, especially patients with BRCA1/2 mutations.

Adding Endocrine Therapy to Dual Anti-HER2 Targeted Therapy Beneficial in HER2+/HR+ Metastatic Breast Cancer

The current first-line standard of care for HER2+ metastatic breast cancer is dual anti-HER2 targeted therapy plus chemotherapy, with consideration for maintenance treatment with anti-HER2 therapy and ET for patients with HR+ and HER2+ metastatic breast cancer. The potential benefit of adding ET for patients with HR+/HER2+ metastatic breast cancer has been reported previously, but data overall are limited. This study analyzed the real-world data of 147 patients with HR+/HER2+ metastatic breast cancer from a prospective registry and who received first-line chemotherapy plus trastuzumab and pertuzumab with (n = 91) or without (n = 56) concurrent ET. The findings showed that adding ET resulted in a significant improvement in 5-year progression-free survival (PFS) (hazard ratio 0.59; P = .031) and overall survival (hazard ratio 0.52; P = .018) compared with not adding ET. No new safety concerns were identified when combining HER2+ targeted therapy and ET. While this is a small retrospective analysis, results are certainly encouraging and support the addition of ET to dual anti-HER2 therapy as maintenance therapy post chemotherapy in this subset of patients.

High PD-L2 Levels May Predict Worse Clinical Outcomes in ER+ Breast Cancer

Programmed cell death-1 ligand-2 (PD-L2) is a second ligand for programmed cell death-1 (PD-1) and inhibits T-cell activation. A retrospective study including patients with estrogen receptor–positive (ER+) breast cancer looked at PD-L2 protein levels in cancer cells and stromal cells of therapy-naive, locoregional ER+ breast cancer in the main study cohort (n = 684) and in an independent validation cohort (n = 273), and correlated findings with PFS. High levels of PD-L2 protein were present in up to one third (33%) of ER+ tumors and were associated with shorter PFS in the entire cohort of patients with ER+ breast cancer (hazard ratio 2.0; P < .001) and in the subgroup of patients treated with adjuvant chemotherapy (hazard ratio 3.4; P < .001). A multivariable analysis showed that high levels of PD-L2 were an independent prognostic marker in ER+ patients. These findings suggest that high PD-L2 is associated with unfavorable prognosis in ER+ breast cancer and may be a potential biomarker of response to checkpoint inhibitors.

Additional References

1. Francis PA, Pagani O, Fleming GF, et al for the SOFT and TEXT Investigators and the International Breast Cancer Study Group. Tailoring adjuvant endocrine therapy for premenopausal breast cancer. N Engl J Med. 2018;379:122-137. Doi: 10.1056/NEJMoa1803164
2. Li X, You R, Wang X, et al. Effectiveness of prophylactic surgeries in BRCA1 or BRCA2 mutation carriers: A meta-analysis and systematic review. Clin Cancer Res. 2016;22:3971-3981. Doi: 10.1158/1078-0432.CCR-15-1465

A post hoc analysis of the ShortHER trial, including 784 patients with hormone-positive (HR+) and human epidermal growth factor receptor 2–positive (HER2+) early breast cancer who received adjuvant trastuzumab plus chemotherapy, showed that adjuvant endocrine therapy (ET) with an aromatase inhibitor (AI) was associated with better outcomes than tamoxifen (TAM) or TAM and AI (TAM-AI) in this population. Disease-free survival rates at 8 years were 86.4% for AI vs 79.7% for the TAM/TAM-AI groups, with an absolute difference of 6.7% (log-rank P = .013). This effect was seen independently of menopausal status in a multivariate analysis.

In the exploratory analysis focusing on the premenopausal patients, the addition of gonadotropin-releasing hormone to ET was associated with a significantly better disease-free survival. This was also noted in an exploratory subgroup analysis of the SOFT trial,^[1] which showed greater benefit from the addition of ovarian suppression to TAM, as compared with TAM alone, among women with HER2+ disease (hazard ratio 0.41; 95% CI 0.22-0.75).

It is important to note that not all patients in the ShortHER trial received the standard-of-care duration of adjuvant trastuzumab; half of them received only 9-week treatment as opposed to the standard 12 months of adjuvant therapy. It is unclear whether this difference in adjuvant therapy could have affected the results, although the disease-free survival multivariate analysis showed no significant effect of the treatment arm on the role of ET. More studies are needed to verify the optimal adjuvant ET for patients with HR+/HER2+ breast cancer, especially in premenopausal patients.

Contralateral Prophylactic Mastectomy Offers No Survival Advantage in Triple-Negative Breast Cancer

There is insufficient evidence that contralateral prophylactic mastectomy (CPM) improves survival in patients with unilateral triple-negative breast cancer (TNBC). A multi-institutional database study, including 796 patients with TNBC, of which 15.5% underwent CPM, showed that CPM did not offer survival benefit to patients with unilateral TNBC. Women who underwent CPM were more likely to be White (P < .001), younger (P < .001), and had had genetic testing performed (P < .001). While there was a borderline improvement in 5-year unadjusted overall survival for patients undergoing CPM compared with no CPM overall (95.1% vs 85.0%; P = .05), no significant improvement was observed for local recurrence-free survival (P = .40) or distant recurrence-free survival (P = .37). Very few (n = 15/673, 2.2%) of the no-CPM patients developed a new primary breast cancer; 3 of the 15 patients were known BRCA1 or BRCA2 mutation carriers. Among the genetic mutation carriers, 5-year overall survival was 97.2% for CPM vs 84.1% for no CPM (P = .35). This study did not demonstrate any statistically significant survival difference between CPM compared with no CPM, regardless of the presence of a BRCA mutation, although prior studies have shown improved outcomes for CPM in BRCA mutation carriers.^[2] Larger prospective studies are needed to evaluate the potential benefit of CPM among patients with TNBC, especially patients with BRCA1/2 mutations.

Adding Endocrine Therapy to Dual Anti-HER2 Targeted Therapy Beneficial in HER2+/HR+ Metastatic Breast Cancer

The current first-line standard of care for HER2+ metastatic breast cancer is dual anti-HER2 targeted therapy plus chemotherapy, with consideration for maintenance treatment with anti-HER2 therapy and ET for patients with HR+ and HER2+ metastatic breast cancer. The potential benefit of adding ET for patients with HR+/HER2+ metastatic breast cancer has been reported previously, but data overall are limited. This study analyzed the real-world data of 147 patients with HR+/HER2+ metastatic breast cancer from a prospective registry and who received first-line chemotherapy plus trastuzumab and pertuzumab with (n = 91) or without (n = 56) concurrent ET. The findings showed that adding ET resulted in a significant improvement in 5-year progression-free survival (PFS) (hazard ratio 0.59; P = .031) and overall survival (hazard ratio 0.52; P = .018) compared with not adding ET. No new safety concerns were identified when combining HER2+ targeted therapy and ET. While this is a small retrospective analysis, results are certainly encouraging and support the addition of ET to dual anti-HER2 therapy as maintenance therapy post chemotherapy in this subset of patients.

High PD-L2 Levels May Predict Worse Clinical Outcomes in ER+ Breast Cancer

Programmed cell death-1 ligand-2 (PD-L2) is a second ligand for programmed cell death-1 (PD-1) and inhibits T-cell activation. A retrospective study including patients with estrogen receptor–positive (ER+) breast cancer looked at PD-L2 protein levels in cancer cells and stromal cells of therapy-naive, locoregional ER+ breast cancer in the main study cohort (n = 684) and in an independent validation cohort (n = 273), and correlated findings with PFS. High levels of PD-L2 protein were present in up to one third (33%) of ER+ tumors and were associated with shorter PFS in the entire cohort of patients with ER+ breast cancer (hazard ratio 2.0; P < .001) and in the subgroup of patients treated with adjuvant chemotherapy (hazard ratio 3.4; P < .001). A multivariable analysis showed that high levels of PD-L2 were an independent prognostic marker in ER+ patients. These findings suggest that high PD-L2 is associated with unfavorable prognosis in ER+ breast cancer and may be a potential biomarker of response to checkpoint inhibitors.

Additional References

1. Francis PA, Pagani O, Fleming GF, et al for the SOFT and TEXT Investigators and the International Breast Cancer Study Group. Tailoring adjuvant endocrine therapy for premenopausal breast cancer. N Engl J Med. 2018;379:122-137. Doi: 10.1056/NEJMoa1803164
2. Li X, You R, Wang X, et al. Effectiveness of prophylactic surgeries in BRCA1 or BRCA2 mutation carriers: A meta-analysis and systematic review. Clin Cancer Res. 2016;22:3971-3981. Doi: 10.1158/1078-0432.CCR-15-1465

Treatment strategies designed to improve or maintain efficacy while minimizing toxicity are desired by both patients and healthcare providers. Neoadjuvant endocrine therapy (NET) represents a therapeutic option for certain patients with luminal breast cancers who may not be candidates for chemotherapy because of comorbidities or preferences to avoid certain treatments. Furthermore, studies have demonstrated tumor or nodal downstaging with NET, as well as the ability of genomic assays to predict clinical response to NET and its association with breast-conserving therapy (BCT).^[4,5] The phase 2 ACOSOG Z1031 trial reported outcomes among 509 women with clinical stage II or III estrogen receptor (ER)–positive breast cancer who received an aromatase inhibitor (AI; exemestane, letrozole, or anastrozole) for 16-18 weeks before surgery. A total of 67.2% of patients had BCT, and of the patients thought to require mastectomy or have inoperable breast cancer at presentation (N = 226), 50.4% were able to have BCT. The pCR rate was low (1%); however, the 5-year cumulative incidence rate for local-regional recurrence was estimated at 1.53% (Hunt et al). This study supports the consideration of NET for select patients, demonstrating a favorable impact on surgery and local-regional recurrence rates. It is also thought-provoking in terms of identifying predictors of response to NET and other novel therapies that can be combined with endocrine therapy in the neoadjuvant space.

The CLEOPATRA trial has established a regimen of docetaxel/trastuzumab/pertuzumab as standard first-line treatment for human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer with superior progression-free survival (PFS) and overall survival (OS) compared with a docetaxel/trastuzumab regimen. Crosstalk between HER2 and ER signaling pathways has been implicated in resistance to anti-HER2 and endocrine therapies. Real-world data have shown that the addition of endocrine therapy to first-line dual anti-HER2-targeted therapy post chemotherapy in HER+/hormone receptor positive (HR+) metastatic breast cancer was associated with benefits in PFS and OS.^[6] The phase 2 PERTAIN trial randomly assigned 258 patients with HER2+/HR+ metastatic breast cancer to receive pertuzumab/trastuzumab plus an AI or trastuzumab/AI, with induction chemotherapy given at the investigator’s discretion. At a median follow-up of > 6 years, the PFS benefit seen with the addition of pertuzumab was maintained (20.6 vs 15.8 months in the trastuzumab/AI arm; stratified hazard ratio 0.67; P = .006). Although there was not a statistically significant difference in median OS (60.2 months in the pertuzumab/trastuzumab/AI arm vs 57.2 months in the trastuzumab/AI arm; stratified hazard ratio 1.05; P = .78), the effect of pertuzumab was potentially amplified in those without induction chemotherapy (26.6 vs 12.5 months) (Arpino et al). These data provide further support for the addition of pertuzumab to trastuzumab in the first-line treatment setting for HER2+ metastatic breast cancer and suggest that some patients may benefit from dual HER2 blockade with endocrine therapy (without chemotherapy).

Additional References

1. Schmid P, Cortes J, Pusztai L, et al, for the KEYNOTE-522 Investigators. Pembrolizumab for early triple-negative breast cancer. N Engl J Med. 2020;382:810-821. Doi: 10.1056/NEJMoa1910549
2. Schmid P, Cortes J, Dent R, et al, for the KEYNOTE-522 Investigators. Event-free survival with pembrolizumab in early triple-negative breast cancer. N Engl J Med. 2022;386:556-567. Doi: 10.1056/NEJMoa2112651
3. Loibl S, Untch M, Burchardi N, et al. A randomised phase II study investigating durvalumab in addition to an anthracycline taxane-based neoadjuvant therapy in early triple-negative breast cancer: Clinical results and biomarker analysis of GeparNuevo study. Ann Oncol. 2019;30:1279-1288. Doi: 10.1093/annonc/mdz158
4. Cao L, Sugumar K, Keller E, et al. Neoadjuvant endocrine therapy as an alternative to neoadjuvant chemotherapy among hormone receptor-positive breast cancer patients: Pathologic and surgical outcomes. Ann Surg Oncol. 2021;28:5730-5741. Doi: 10.1245/s10434-021-10459-3
5. Iwata H, Masuda N, Yamamoto Y, et al. Validation of the 21-gene test as a predictor of clinical response to neoadjuvant hormonal therapy for ER+, HER2-negative breast cancer: The TransNEOS study. Breast Cancer Res Treat. 2019;173:123-133. Doi: 10.1007/s10549-018-4964-y
6. Loft M, Lok SW, De Boer R, et al. Addition of endocrine therapy to dual anti-HER2 targeted therapy in initial treatment of HER2+/HR+ metastatic breast cancer. Breast Cancer Res Treat. 2023;198:67-74. Doi: 10.1007/s10549-022-06856-1

Treatment strategies designed to improve or maintain efficacy while minimizing toxicity are desired by both patients and healthcare providers. Neoadjuvant endocrine therapy (NET) represents a therapeutic option for certain patients with luminal breast cancers who may not be candidates for chemotherapy because of comorbidities or preferences to avoid certain treatments. Furthermore, studies have demonstrated tumor or nodal downstaging with NET, as well as the ability of genomic assays to predict clinical response to NET and its association with breast-conserving therapy (BCT).^[4,5] The phase 2 ACOSOG Z1031 trial reported outcomes among 509 women with clinical stage II or III estrogen receptor (ER)–positive breast cancer who received an aromatase inhibitor (AI; exemestane, letrozole, or anastrozole) for 16-18 weeks before surgery. A total of 67.2% of patients had BCT, and of the patients thought to require mastectomy or have inoperable breast cancer at presentation (N = 226), 50.4% were able to have BCT. The pCR rate was low (1%); however, the 5-year cumulative incidence rate for local-regional recurrence was estimated at 1.53% (Hunt et al). This study supports the consideration of NET for select patients, demonstrating a favorable impact on surgery and local-regional recurrence rates. It is also thought-provoking in terms of identifying predictors of response to NET and other novel therapies that can be combined with endocrine therapy in the neoadjuvant space.

The CLEOPATRA trial has established a regimen of docetaxel/trastuzumab/pertuzumab as standard first-line treatment for human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer with superior progression-free survival (PFS) and overall survival (OS) compared with a docetaxel/trastuzumab regimen. Crosstalk between HER2 and ER signaling pathways has been implicated in resistance to anti-HER2 and endocrine therapies. Real-world data have shown that the addition of endocrine therapy to first-line dual anti-HER2-targeted therapy post chemotherapy in HER+/hormone receptor positive (HR+) metastatic breast cancer was associated with benefits in PFS and OS.^[6] The phase 2 PERTAIN trial randomly assigned 258 patients with HER2+/HR+ metastatic breast cancer to receive pertuzumab/trastuzumab plus an AI or trastuzumab/AI, with induction chemotherapy given at the investigator’s discretion. At a median follow-up of > 6 years, the PFS benefit seen with the addition of pertuzumab was maintained (20.6 vs 15.8 months in the trastuzumab/AI arm; stratified hazard ratio 0.67; P = .006). Although there was not a statistically significant difference in median OS (60.2 months in the pertuzumab/trastuzumab/AI arm vs 57.2 months in the trastuzumab/AI arm; stratified hazard ratio 1.05; P = .78), the effect of pertuzumab was potentially amplified in those without induction chemotherapy (26.6 vs 12.5 months) (Arpino et al). These data provide further support for the addition of pertuzumab to trastuzumab in the first-line treatment setting for HER2+ metastatic breast cancer and suggest that some patients may benefit from dual HER2 blockade with endocrine therapy (without chemotherapy).

Additional References

1. Schmid P, Cortes J, Pusztai L, et al, for the KEYNOTE-522 Investigators. Pembrolizumab for early triple-negative breast cancer. N Engl J Med. 2020;382:810-821. Doi: 10.1056/NEJMoa1910549
2. Schmid P, Cortes J, Dent R, et al, for the KEYNOTE-522 Investigators. Event-free survival with pembrolizumab in early triple-negative breast cancer. N Engl J Med. 2022;386:556-567. Doi: 10.1056/NEJMoa2112651
3. Loibl S, Untch M, Burchardi N, et al. A randomised phase II study investigating durvalumab in addition to an anthracycline taxane-based neoadjuvant therapy in early triple-negative breast cancer: Clinical results and biomarker analysis of GeparNuevo study. Ann Oncol. 2019;30:1279-1288. Doi: 10.1093/annonc/mdz158
4. Cao L, Sugumar K, Keller E, et al. Neoadjuvant endocrine therapy as an alternative to neoadjuvant chemotherapy among hormone receptor-positive breast cancer patients: Pathologic and surgical outcomes. Ann Surg Oncol. 2021;28:5730-5741. Doi: 10.1245/s10434-021-10459-3
5. Iwata H, Masuda N, Yamamoto Y, et al. Validation of the 21-gene test as a predictor of clinical response to neoadjuvant hormonal therapy for ER+, HER2-negative breast cancer: The TransNEOS study. Breast Cancer Res Treat. 2019;173:123-133. Doi: 10.1007/s10549-018-4964-y
6. Loft M, Lok SW, De Boer R, et al. Addition of endocrine therapy to dual anti-HER2 targeted therapy in initial treatment of HER2+/HR+ metastatic breast cancer. Breast Cancer Res Treat. 2023;198:67-74. Doi: 10.1007/s10549-022-06856-1

Treatment strategies designed to improve or maintain efficacy while minimizing toxicity are desired by both patients and healthcare providers. Neoadjuvant endocrine therapy (NET) represents a therapeutic option for certain patients with luminal breast cancers who may not be candidates for chemotherapy because of comorbidities or preferences to avoid certain treatments. Furthermore, studies have demonstrated tumor or nodal downstaging with NET, as well as the ability of genomic assays to predict clinical response to NET and its association with breast-conserving therapy (BCT).^[4,5] The phase 2 ACOSOG Z1031 trial reported outcomes among 509 women with clinical stage II or III estrogen receptor (ER)–positive breast cancer who received an aromatase inhibitor (AI; exemestane, letrozole, or anastrozole) for 16-18 weeks before surgery. A total of 67.2% of patients had BCT, and of the patients thought to require mastectomy or have inoperable breast cancer at presentation (N = 226), 50.4% were able to have BCT. The pCR rate was low (1%); however, the 5-year cumulative incidence rate for local-regional recurrence was estimated at 1.53% (Hunt et al). This study supports the consideration of NET for select patients, demonstrating a favorable impact on surgery and local-regional recurrence rates. It is also thought-provoking in terms of identifying predictors of response to NET and other novel therapies that can be combined with endocrine therapy in the neoadjuvant space.

The CLEOPATRA trial has established a regimen of docetaxel/trastuzumab/pertuzumab as standard first-line treatment for human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer with superior progression-free survival (PFS) and overall survival (OS) compared with a docetaxel/trastuzumab regimen. Crosstalk between HER2 and ER signaling pathways has been implicated in resistance to anti-HER2 and endocrine therapies. Real-world data have shown that the addition of endocrine therapy to first-line dual anti-HER2-targeted therapy post chemotherapy in HER+/hormone receptor positive (HR+) metastatic breast cancer was associated with benefits in PFS and OS.^[6] The phase 2 PERTAIN trial randomly assigned 258 patients with HER2+/HR+ metastatic breast cancer to receive pertuzumab/trastuzumab plus an AI or trastuzumab/AI, with induction chemotherapy given at the investigator’s discretion. At a median follow-up of > 6 years, the PFS benefit seen with the addition of pertuzumab was maintained (20.6 vs 15.8 months in the trastuzumab/AI arm; stratified hazard ratio 0.67; P = .006). Although there was not a statistically significant difference in median OS (60.2 months in the pertuzumab/trastuzumab/AI arm vs 57.2 months in the trastuzumab/AI arm; stratified hazard ratio 1.05; P = .78), the effect of pertuzumab was potentially amplified in those without induction chemotherapy (26.6 vs 12.5 months) (Arpino et al). These data provide further support for the addition of pertuzumab to trastuzumab in the first-line treatment setting for HER2+ metastatic breast cancer and suggest that some patients may benefit from dual HER2 blockade with endocrine therapy (without chemotherapy).

Additional References

1. Schmid P, Cortes J, Pusztai L, et al, for the KEYNOTE-522 Investigators. Pembrolizumab for early triple-negative breast cancer. N Engl J Med. 2020;382:810-821. Doi: 10.1056/NEJMoa1910549
2. Schmid P, Cortes J, Dent R, et al, for the KEYNOTE-522 Investigators. Event-free survival with pembrolizumab in early triple-negative breast cancer. N Engl J Med. 2022;386:556-567. Doi: 10.1056/NEJMoa2112651
3. Loibl S, Untch M, Burchardi N, et al. A randomised phase II study investigating durvalumab in addition to an anthracycline taxane-based neoadjuvant therapy in early triple-negative breast cancer: Clinical results and biomarker analysis of GeparNuevo study. Ann Oncol. 2019;30:1279-1288. Doi: 10.1093/annonc/mdz158
4. Cao L, Sugumar K, Keller E, et al. Neoadjuvant endocrine therapy as an alternative to neoadjuvant chemotherapy among hormone receptor-positive breast cancer patients: Pathologic and surgical outcomes. Ann Surg Oncol. 2021;28:5730-5741. Doi: 10.1245/s10434-021-10459-3
5. Iwata H, Masuda N, Yamamoto Y, et al. Validation of the 21-gene test as a predictor of clinical response to neoadjuvant hormonal therapy for ER+, HER2-negative breast cancer: The TransNEOS study. Breast Cancer Res Treat. 2019;173:123-133. Doi: 10.1007/s10549-018-4964-y
6. Loft M, Lok SW, De Boer R, et al. Addition of endocrine therapy to dual anti-HER2 targeted therapy in initial treatment of HER2+/HR+ metastatic breast cancer. Breast Cancer Res Treat. 2023;198:67-74. Doi: 10.1007/s10549-022-06856-1

Another study caught my attention this month for having presented a lot of information with no clinically important conclusions. In "Mode of Delivery and Offspring Atopic Dermatitis in a Swedish Nationwide Study," Mubanga and colleagues studied 1.4 million children! With that many participants, they were almost certain to find associations that were statistically significant and clinically irrelevant. They reported that children born by instrumental vaginal delivery, emergency caesarean section, and elective caesarean section were at a higher risk for AD compared with those born by uncomplicated vaginal delivery. They failed to report the absolute magnitude of the associations, which were undoubtedly so small as to be clinically meaningless. Even if the observed association were not due to some hidden bias, the association is not anything that would change treatment in any way.

On the other hand, the small, open label registry analysis, "Experiences From Daily Practice of Upadacitinib Treatment on Atopic Dermatitis With a Focus on Hand Eczema: Results From the BioDay Registry," published by Kamphuis and colleagues, is of much greater value, reporting the effectiveness and safety of upadacitinib on hand eczema. Not surprisingly, there were large improvements in the investigators' assessments of the dermatitis and in patients' quality of life. This small study is informative about efficacy; it is too small, though, to evaluate how frequently rare severe adverse events occur.

The use of probiotics to safely improve skin disease is such an appealing concept, yet it sounds a lot like hocus-pocus to me. Feíto-Rodríguez and colleagues report in the journal Clinical and Experimental Dermatology that a probiotic mixture of Bifidobacterium lactis, Bifidobacterium longum, and Lactobacillus casei improved atopic dermatitis more than did placebo. The findings are not compelling. Differences were small. Rates of being clear or almost clear weren't reported. We can get atopic dermatitis to clear up in a few days with topical triamcinolone (if we can get patients to use it); so far, the effects of probiotics on the presumed gut-immune system-skin axis seem very much underwhelming.

Another study caught my attention this month for having presented a lot of information with no clinically important conclusions. In "Mode of Delivery and Offspring Atopic Dermatitis in a Swedish Nationwide Study," Mubanga and colleagues studied 1.4 million children! With that many participants, they were almost certain to find associations that were statistically significant and clinically irrelevant. They reported that children born by instrumental vaginal delivery, emergency caesarean section, and elective caesarean section were at a higher risk for AD compared with those born by uncomplicated vaginal delivery. They failed to report the absolute magnitude of the associations, which were undoubtedly so small as to be clinically meaningless. Even if the observed association were not due to some hidden bias, the association is not anything that would change treatment in any way.

On the other hand, the small, open label registry analysis, "Experiences From Daily Practice of Upadacitinib Treatment on Atopic Dermatitis With a Focus on Hand Eczema: Results From the BioDay Registry," published by Kamphuis and colleagues, is of much greater value, reporting the effectiveness and safety of upadacitinib on hand eczema. Not surprisingly, there were large improvements in the investigators' assessments of the dermatitis and in patients' quality of life. This small study is informative about efficacy; it is too small, though, to evaluate how frequently rare severe adverse events occur.

The use of probiotics to safely improve skin disease is such an appealing concept, yet it sounds a lot like hocus-pocus to me. Feíto-Rodríguez and colleagues report in the journal Clinical and Experimental Dermatology that a probiotic mixture of Bifidobacterium lactis, Bifidobacterium longum, and Lactobacillus casei improved atopic dermatitis more than did placebo. The findings are not compelling. Differences were small. Rates of being clear or almost clear weren't reported. We can get atopic dermatitis to clear up in a few days with topical triamcinolone (if we can get patients to use it); so far, the effects of probiotics on the presumed gut-immune system-skin axis seem very much underwhelming.

Another study caught my attention this month for having presented a lot of information with no clinically important conclusions. In "Mode of Delivery and Offspring Atopic Dermatitis in a Swedish Nationwide Study," Mubanga and colleagues studied 1.4 million children! With that many participants, they were almost certain to find associations that were statistically significant and clinically irrelevant. They reported that children born by instrumental vaginal delivery, emergency caesarean section, and elective caesarean section were at a higher risk for AD compared with those born by uncomplicated vaginal delivery. They failed to report the absolute magnitude of the associations, which were undoubtedly so small as to be clinically meaningless. Even if the observed association were not due to some hidden bias, the association is not anything that would change treatment in any way.

On the other hand, the small, open label registry analysis, "Experiences From Daily Practice of Upadacitinib Treatment on Atopic Dermatitis With a Focus on Hand Eczema: Results From the BioDay Registry," published by Kamphuis and colleagues, is of much greater value, reporting the effectiveness and safety of upadacitinib on hand eczema. Not surprisingly, there were large improvements in the investigators' assessments of the dermatitis and in patients' quality of life. This small study is informative about efficacy; it is too small, though, to evaluate how frequently rare severe adverse events occur.

The use of probiotics to safely improve skin disease is such an appealing concept, yet it sounds a lot like hocus-pocus to me. Feíto-Rodríguez and colleagues report in the journal Clinical and Experimental Dermatology that a probiotic mixture of Bifidobacterium lactis, Bifidobacterium longum, and Lactobacillus casei improved atopic dermatitis more than did placebo. The findings are not compelling. Differences were small. Rates of being clear or almost clear weren't reported. We can get atopic dermatitis to clear up in a few days with topical triamcinolone (if we can get patients to use it); so far, the effects of probiotics on the presumed gut-immune system-skin axis seem very much underwhelming.