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In this current age of mass misinformation and disinformation on the Internet, a tongue-in-cheek study that evaluated beliefs and attitudes toward cancer among conspiracy theorists and people who oppose vaccinations has received some harsh criticism.

The study, entitled, “Everything Causes Cancer? Beliefs and Attitudes Towards Cancer Prevention Among Anti-Vaxxers, Flat Earthers, and Reptilian Conspiracists: Online Cross Sectional Survey,” was published in the Christmas 2022 issue of The British Medical Journal (BMJ).

The authors explain that they set out to evaluate “the patterns of beliefs about cancer among people who believed in conspiracies, rejected the COVID-19 vaccine, or preferred alternative medicine.”

They sought such people on social media and online chat platforms and asked them questions about real and mythical causes of cancer.

Almost half of survey participants agreed with the statement, “It seems like everything causes cancer.”

Overall, among all participants, awareness of the actual causes of cancer was greater than awareness of the mythical causes of cancer, the authors report. However, awareness of the actual causes of cancer was lower among the unvaccinated and members of conspiracy groups than among their counterparts.

The authors are concerned that their findings suggest “a direct connection between digital misinformation and consequent potential erroneous health decisions, which may represent a further preventable fraction of cancer.”
 

Backlash and criticism

The study “highlights the difficulty society encounters in distinguishing the actual causes of cancer from mythical causes,” The BMJ commented on Twitter.

However, both the study and the journal received some backlash.

This is a “horrible article seeking to smear people with concerns about COVID vaccines,” commented Clare Craig, a British consultant pathologist who specializes in cancer diagnostics.

The study and its methodology were also harshly criticized on Twitter by Normal Fenton, professor of risk information management at the Queen Mary University of London.

The senior author of the study, Laura Costas, a medical epidemiologist with the Catalan Institute of Oncology, Barcelona, told this news organization that the naysayers on social media, many of whom focused their comments on the COVID-19 vaccine, prove the purpose of the study – that misinformation spreads widely on the internet.

“Most comments focused on spreading COVID-19 myths, which were not the direct subject of the study, and questioned the motivations of BMJ authors and the scientific community, assuming they had a common malevolent hidden agenda,” Ms. Costas said.

“They stated the need of having critical thinking, a trait in common with the scientific method, but dogmatically dismissed any information that comes from official sources,” she added.

Ms. Costas commented that “society encounters difficulty in differentiating actual from mythical causes of cancer owing to mass information. We therefore planned this study with a certain satire, which is in line with the essence of The BMJ Christmas issue.”

The BMJ has a long history of publishing a lighthearted Christmas edition full of original, satirical, and nontraditional studies. Previous years have seen studies that explored potential harms from holly and ivy, survival time of chocolates on hospital wards, and the question, “Were James Bond’s drinks shaken because of alcohol induced tremor?”
 

Study details

Ms. Costas and colleagues sought participants for their survey from online forums that included 4chan and Reddit, which are known for their controversial content posted by anonymous users. Data were also collected from ForoCoches and HispaChan, well-known Spanish online forums. These online sites were intentionally chosen because researchers thought “conspiracy beliefs would be more prevalent,” according to Ms. Costas.

Across the multiple forums, there were 1,494 participants. Of these, 209 participants were unvaccinated against COVID-19, 112 preferred alternatives rather than conventional medicine, and 62 reported that they believed the earth was flat or believed that humanoids take reptilian forms to manipulate human societies.

The team then sought to assess beliefs about actual and mythical (nonestablished) causes of cancer by presenting the participants with the closed risk factor questions on two validated scales – the Cancer Awareness Measure (CAM) and CAM–Mythical Causes Scale (CAM-MYCS).

Responses to both were recorded on a five-point scale; answers ranged from “strongly disagree” to “strongly agree.”

The CAM assesses cancer risk perceptions of 11 established risk factors for cancer: smoking actively or passively, consuming alcohol, low levels of physical activity, consuming red or processed meat, getting sunburnt as a child, family history of cancer, human papillomavirus infection, being overweight, age greater than or equal to 70 years, and low vegetable and fruit consumption.

The CAM-MYCS measure includes 12 questions on risk perceptions of mythical causes of cancer – nonestablished causes that are commonly believed to cause cancer but for which there is no supporting scientific evidence, the authors explain. These items include drinking from plastic bottles; eating food containing artificial sweeteners or additives and genetically modified food; using microwave ovens, aerosol containers, mobile phones, and cleaning products; living near power lines; feeling stressed; experiencing physical trauma; and being exposed to electromagnetic frequencies/non-ionizing radiation, such as wi-fi networks, radio, and television.

The most endorsed mythical causes of cancer were eating food containing additives (63.9%) or sweeteners (50.7%), feeling stressed (59.7%), and eating genetically modified foods (38.4%).

A version of this article first appeared on Medscape.com.

In this current age of mass misinformation and disinformation on the Internet, a tongue-in-cheek study that evaluated beliefs and attitudes toward cancer among conspiracy theorists and people who oppose vaccinations has received some harsh criticism.

The study, entitled, “Everything Causes Cancer? Beliefs and Attitudes Towards Cancer Prevention Among Anti-Vaxxers, Flat Earthers, and Reptilian Conspiracists: Online Cross Sectional Survey,” was published in the Christmas 2022 issue of The British Medical Journal (BMJ).

The authors explain that they set out to evaluate “the patterns of beliefs about cancer among people who believed in conspiracies, rejected the COVID-19 vaccine, or preferred alternative medicine.”

They sought such people on social media and online chat platforms and asked them questions about real and mythical causes of cancer.

Almost half of survey participants agreed with the statement, “It seems like everything causes cancer.”

Overall, among all participants, awareness of the actual causes of cancer was greater than awareness of the mythical causes of cancer, the authors report. However, awareness of the actual causes of cancer was lower among the unvaccinated and members of conspiracy groups than among their counterparts.

The authors are concerned that their findings suggest “a direct connection between digital misinformation and consequent potential erroneous health decisions, which may represent a further preventable fraction of cancer.”
 

Backlash and criticism

The study “highlights the difficulty society encounters in distinguishing the actual causes of cancer from mythical causes,” The BMJ commented on Twitter.

However, both the study and the journal received some backlash.

This is a “horrible article seeking to smear people with concerns about COVID vaccines,” commented Clare Craig, a British consultant pathologist who specializes in cancer diagnostics.

The study and its methodology were also harshly criticized on Twitter by Normal Fenton, professor of risk information management at the Queen Mary University of London.

The senior author of the study, Laura Costas, a medical epidemiologist with the Catalan Institute of Oncology, Barcelona, told this news organization that the naysayers on social media, many of whom focused their comments on the COVID-19 vaccine, prove the purpose of the study – that misinformation spreads widely on the internet.

“Most comments focused on spreading COVID-19 myths, which were not the direct subject of the study, and questioned the motivations of BMJ authors and the scientific community, assuming they had a common malevolent hidden agenda,” Ms. Costas said.

“They stated the need of having critical thinking, a trait in common with the scientific method, but dogmatically dismissed any information that comes from official sources,” she added.

Ms. Costas commented that “society encounters difficulty in differentiating actual from mythical causes of cancer owing to mass information. We therefore planned this study with a certain satire, which is in line with the essence of The BMJ Christmas issue.”

The BMJ has a long history of publishing a lighthearted Christmas edition full of original, satirical, and nontraditional studies. Previous years have seen studies that explored potential harms from holly and ivy, survival time of chocolates on hospital wards, and the question, “Were James Bond’s drinks shaken because of alcohol induced tremor?”
 

Study details

Ms. Costas and colleagues sought participants for their survey from online forums that included 4chan and Reddit, which are known for their controversial content posted by anonymous users. Data were also collected from ForoCoches and HispaChan, well-known Spanish online forums. These online sites were intentionally chosen because researchers thought “conspiracy beliefs would be more prevalent,” according to Ms. Costas.

Across the multiple forums, there were 1,494 participants. Of these, 209 participants were unvaccinated against COVID-19, 112 preferred alternatives rather than conventional medicine, and 62 reported that they believed the earth was flat or believed that humanoids take reptilian forms to manipulate human societies.

The team then sought to assess beliefs about actual and mythical (nonestablished) causes of cancer by presenting the participants with the closed risk factor questions on two validated scales – the Cancer Awareness Measure (CAM) and CAM–Mythical Causes Scale (CAM-MYCS).

Responses to both were recorded on a five-point scale; answers ranged from “strongly disagree” to “strongly agree.”

The CAM assesses cancer risk perceptions of 11 established risk factors for cancer: smoking actively or passively, consuming alcohol, low levels of physical activity, consuming red or processed meat, getting sunburnt as a child, family history of cancer, human papillomavirus infection, being overweight, age greater than or equal to 70 years, and low vegetable and fruit consumption.

The CAM-MYCS measure includes 12 questions on risk perceptions of mythical causes of cancer – nonestablished causes that are commonly believed to cause cancer but for which there is no supporting scientific evidence, the authors explain. These items include drinking from plastic bottles; eating food containing artificial sweeteners or additives and genetically modified food; using microwave ovens, aerosol containers, mobile phones, and cleaning products; living near power lines; feeling stressed; experiencing physical trauma; and being exposed to electromagnetic frequencies/non-ionizing radiation, such as wi-fi networks, radio, and television.

The most endorsed mythical causes of cancer were eating food containing additives (63.9%) or sweeteners (50.7%), feeling stressed (59.7%), and eating genetically modified foods (38.4%).

A version of this article first appeared on Medscape.com.

In this current age of mass misinformation and disinformation on the Internet, a tongue-in-cheek study that evaluated beliefs and attitudes toward cancer among conspiracy theorists and people who oppose vaccinations has received some harsh criticism.

The study, entitled, “Everything Causes Cancer? Beliefs and Attitudes Towards Cancer Prevention Among Anti-Vaxxers, Flat Earthers, and Reptilian Conspiracists: Online Cross Sectional Survey,” was published in the Christmas 2022 issue of The British Medical Journal (BMJ).

The authors explain that they set out to evaluate “the patterns of beliefs about cancer among people who believed in conspiracies, rejected the COVID-19 vaccine, or preferred alternative medicine.”

They sought such people on social media and online chat platforms and asked them questions about real and mythical causes of cancer.

Almost half of survey participants agreed with the statement, “It seems like everything causes cancer.”

Overall, among all participants, awareness of the actual causes of cancer was greater than awareness of the mythical causes of cancer, the authors report. However, awareness of the actual causes of cancer was lower among the unvaccinated and members of conspiracy groups than among their counterparts.

The authors are concerned that their findings suggest “a direct connection between digital misinformation and consequent potential erroneous health decisions, which may represent a further preventable fraction of cancer.”
 

Backlash and criticism

The study “highlights the difficulty society encounters in distinguishing the actual causes of cancer from mythical causes,” The BMJ commented on Twitter.

However, both the study and the journal received some backlash.

This is a “horrible article seeking to smear people with concerns about COVID vaccines,” commented Clare Craig, a British consultant pathologist who specializes in cancer diagnostics.

The study and its methodology were also harshly criticized on Twitter by Normal Fenton, professor of risk information management at the Queen Mary University of London.

The senior author of the study, Laura Costas, a medical epidemiologist with the Catalan Institute of Oncology, Barcelona, told this news organization that the naysayers on social media, many of whom focused their comments on the COVID-19 vaccine, prove the purpose of the study – that misinformation spreads widely on the internet.

“Most comments focused on spreading COVID-19 myths, which were not the direct subject of the study, and questioned the motivations of BMJ authors and the scientific community, assuming they had a common malevolent hidden agenda,” Ms. Costas said.

“They stated the need of having critical thinking, a trait in common with the scientific method, but dogmatically dismissed any information that comes from official sources,” she added.

Ms. Costas commented that “society encounters difficulty in differentiating actual from mythical causes of cancer owing to mass information. We therefore planned this study with a certain satire, which is in line with the essence of The BMJ Christmas issue.”

The BMJ has a long history of publishing a lighthearted Christmas edition full of original, satirical, and nontraditional studies. Previous years have seen studies that explored potential harms from holly and ivy, survival time of chocolates on hospital wards, and the question, “Were James Bond’s drinks shaken because of alcohol induced tremor?”
 

Study details

Ms. Costas and colleagues sought participants for their survey from online forums that included 4chan and Reddit, which are known for their controversial content posted by anonymous users. Data were also collected from ForoCoches and HispaChan, well-known Spanish online forums. These online sites were intentionally chosen because researchers thought “conspiracy beliefs would be more prevalent,” according to Ms. Costas.

Across the multiple forums, there were 1,494 participants. Of these, 209 participants were unvaccinated against COVID-19, 112 preferred alternatives rather than conventional medicine, and 62 reported that they believed the earth was flat or believed that humanoids take reptilian forms to manipulate human societies.

The team then sought to assess beliefs about actual and mythical (nonestablished) causes of cancer by presenting the participants with the closed risk factor questions on two validated scales – the Cancer Awareness Measure (CAM) and CAM–Mythical Causes Scale (CAM-MYCS).

Responses to both were recorded on a five-point scale; answers ranged from “strongly disagree” to “strongly agree.”

The CAM assesses cancer risk perceptions of 11 established risk factors for cancer: smoking actively or passively, consuming alcohol, low levels of physical activity, consuming red or processed meat, getting sunburnt as a child, family history of cancer, human papillomavirus infection, being overweight, age greater than or equal to 70 years, and low vegetable and fruit consumption.

The CAM-MYCS measure includes 12 questions on risk perceptions of mythical causes of cancer – nonestablished causes that are commonly believed to cause cancer but for which there is no supporting scientific evidence, the authors explain. These items include drinking from plastic bottles; eating food containing artificial sweeteners or additives and genetically modified food; using microwave ovens, aerosol containers, mobile phones, and cleaning products; living near power lines; feeling stressed; experiencing physical trauma; and being exposed to electromagnetic frequencies/non-ionizing radiation, such as wi-fi networks, radio, and television.

The most endorsed mythical causes of cancer were eating food containing additives (63.9%) or sweeteners (50.7%), feeling stressed (59.7%), and eating genetically modified foods (38.4%).

A version of this article first appeared on Medscape.com.

The Diagnosis: Pseudoangiomatous Squamous Cell Carcinoma

Pseudoangiomatous squamous cell carcinoma (PSCC), a variant of acantholytic squamous cell carcinoma (SCC), is a rare epithelial neoplasm that can mimic angiosarcoma.¹ Clinically, PSCC presents as a white-gray ulcer or nodular pink tumor on sun-exposed areas, typically on the head and neck. Due to its increased potential for metastasis, this variant of SCC is considered particularly aggressive. Histologically, PSCC shows nests of acantholytic atypical keratinocytes arranged in anastomosing arrays that form pseudovascular or pseudoglandular structures.² Acantholytic spaces frequently are filled with erythrocytes. Immunohistochemically, PSCC tumor cells express classic squamous markers such as cytokeratin (CK) 5 and p63 but not vascular markers such as CD31, CD34, and von Willebrand factor.³ In our patient, histopathology of the lesion revealed invasive nests, lobules, and interconnected columns of well-differentiated squamous tumor cells that emanated from the base of the epidermis. The tumor exhibited acantholysis forming ectatic and slitlike spaces, some of which contained erythrocytes. The neoplastic cells, including those lining pseudovascular spaces, positively stained for CK5 (Figure 1A) and nuclear p63 but lacked reactivity to CD31 (Figure 1B) and CD34, corroborating squamous and not vascular differentiation. Current treatment guidelines include Mohs micrographic surgery, excisional surgery, or radiation.⁴ Our patient’s lesion was completely removed by Mohs micrographic surgery. Three months later, there was no evidence of recurrence.

Angiosarcoma is an aggressive neoplasm associated with a poor prognosis and 5-year survival rate of 30% to 40%. The etiology of angiosarcoma still is unclear, but identified risk factors include prior radiation therapy, lymphedema (Stewart-Treves syndrome), and genetic predisposition.⁵ In the skin, angiosarcoma often occurs in the head and neck region, accounting for 60% of cutaneous cases.^5,6 Early in the disease, most patients present with a bruiselike lesion on the scalp or forehead, often delaying the diagnosis.⁶ As the cancer progresses, tissue infiltration, edema, and hemorrhage contribute to the formation of violaceous nodules, which eventually prompt for biopsy. Angiosarcoma spans a broad histologic spectrum depending on the cytology of malignant cells (eg, spindle, small round, epithelioid) and their capacity for vasoformation. Welldifferentiated angiosarcoma shows retiform slitlike spaces in between collagen bundles that are lined by hyperchromatic hobnailing endothelial cells (Figure 2).⁷ Epithelioid angiosarcoma can be mistaken for SCC.⁸ Immunohistochemically, angiosarcoma stains positively for CD31, CD34, ETS-related gene 1, D2-40, and factor VIII.9 In our patient, the neoplasm was negative for vascular markers CD31 and CD34.

Bacillary angiomatosis (BA), caused by Bartonella henselae, is a rare disease that first was identified in HIV patients with diminished CD4+ T-cell counts. In the skin, BA often manifests as centrally ulcerated, single or clustered, reddish-purple nodules.¹⁰ Histologically, it is characterized by highly vascularized, histiocyterich infiltrates with admixed neutrophils and plasma cells (Figure 3). Capillaries often proliferate in a lobular fashion.¹¹ Atypical cytology with areas of necrosis may mimic angiosarcoma.¹² The pathognomonic feature of BA is the presence of enlarged histiocytes with pink-purplish cytoplasm corresponding to intracytoplasmic aggregates of bacteria, which can be revealed by Warthin-Starry or Grocott-Gomori methenamine-silver staining. Immunohistochemically, proliferative benign capillaries are highlighted by CD34 and CD31, and histiocytes are decorated by CD68.¹² This diagnosis was excluded based on the patient’s history, clinical presentation, and positive staining for CK5 and p63.

Squamoid eccrine ductal carcinoma is an exceedingly rare subtype of eccrine carcinoma that mimics SCC both clinically and histologically.¹³ It most often occurs on the head and neck of elderly patients. This neoplasm can look similar to SCC and its variants, including PSCC. Histologically, squamoid eccrine ductal carcinoma exhibits a biphasic growth pattern.¹⁴ Well-differentiated squamous dysplasia transitions to carcinoma with eccrine duct formation as the tumor percolates deep into the dermis (Figure 4). As a result, superficial skin biopsies often lead to an incorrect diagnosis.¹⁵ Unlike SCC, the risk for locoregional and widespread metastasis is elevated. Identifying ducts in the deep aspect of the tumor is critical, thus immunohistochemical staining for carcinoembryonic antigen and epithelial membrane antigen is paramount for the diagnosis.¹⁵ Pseudoangiomatous SCC will stain negative for carcinoembryonic antigen, as was the case in our patient.

Pseudoepitheliomatous hyperplasia is a benign histologic reaction that can result from trauma, chronic inflammation (ie, pyoderma gangrenosum), tattoo placement, underlying neoplasia or fungal infection, or a spider bite reaction.^14,15 It most commonly is seen as a well-demarcated nodule or plaque associated with scaling or crusting. Papules vary in size from less than 1 cm to several centimeters. Histologically, it is defined by an acanthotic proliferation of the adnexal epithelium and epidermis (Figure 5).^16,17 Irregular strands, cords, and nests of squamoid cells can extend into the dermis.¹⁸ It can closely mimic SCC, but there are a few key differences. Pseudoepitheliomatous hyperplasia will not display atypical mitotic figures or atypical nuclei and will never invade lymphatics or vascular systems.¹⁹ Pseudoepitheliomatous hyperplasia shows identical histology to well-differentiated SCC, and thus clinicopathologic correlation and mindful histologic evaluation are crucial. The presence of an increased influx of neutrophils and histiocytes should prompt for microbial stains or deeper sectioning. A superficial biopsy should be followed by a deep biopsy. In our patient, microorganismal stains were negative.

The Diagnosis: Pseudoangiomatous Squamous Cell Carcinoma

Pseudoangiomatous squamous cell carcinoma (PSCC), a variant of acantholytic squamous cell carcinoma (SCC), is a rare epithelial neoplasm that can mimic angiosarcoma.¹ Clinically, PSCC presents as a white-gray ulcer or nodular pink tumor on sun-exposed areas, typically on the head and neck. Due to its increased potential for metastasis, this variant of SCC is considered particularly aggressive. Histologically, PSCC shows nests of acantholytic atypical keratinocytes arranged in anastomosing arrays that form pseudovascular or pseudoglandular structures.² Acantholytic spaces frequently are filled with erythrocytes. Immunohistochemically, PSCC tumor cells express classic squamous markers such as cytokeratin (CK) 5 and p63 but not vascular markers such as CD31, CD34, and von Willebrand factor.³ In our patient, histopathology of the lesion revealed invasive nests, lobules, and interconnected columns of well-differentiated squamous tumor cells that emanated from the base of the epidermis. The tumor exhibited acantholysis forming ectatic and slitlike spaces, some of which contained erythrocytes. The neoplastic cells, including those lining pseudovascular spaces, positively stained for CK5 (Figure 1A) and nuclear p63 but lacked reactivity to CD31 (Figure 1B) and CD34, corroborating squamous and not vascular differentiation. Current treatment guidelines include Mohs micrographic surgery, excisional surgery, or radiation.⁴ Our patient’s lesion was completely removed by Mohs micrographic surgery. Three months later, there was no evidence of recurrence.

Angiosarcoma is an aggressive neoplasm associated with a poor prognosis and 5-year survival rate of 30% to 40%. The etiology of angiosarcoma still is unclear, but identified risk factors include prior radiation therapy, lymphedema (Stewart-Treves syndrome), and genetic predisposition.⁵ In the skin, angiosarcoma often occurs in the head and neck region, accounting for 60% of cutaneous cases.^5,6 Early in the disease, most patients present with a bruiselike lesion on the scalp or forehead, often delaying the diagnosis.⁶ As the cancer progresses, tissue infiltration, edema, and hemorrhage contribute to the formation of violaceous nodules, which eventually prompt for biopsy. Angiosarcoma spans a broad histologic spectrum depending on the cytology of malignant cells (eg, spindle, small round, epithelioid) and their capacity for vasoformation. Welldifferentiated angiosarcoma shows retiform slitlike spaces in between collagen bundles that are lined by hyperchromatic hobnailing endothelial cells (Figure 2).⁷ Epithelioid angiosarcoma can be mistaken for SCC.⁸ Immunohistochemically, angiosarcoma stains positively for CD31, CD34, ETS-related gene 1, D2-40, and factor VIII.9 In our patient, the neoplasm was negative for vascular markers CD31 and CD34.

Bacillary angiomatosis (BA), caused by Bartonella henselae, is a rare disease that first was identified in HIV patients with diminished CD4+ T-cell counts. In the skin, BA often manifests as centrally ulcerated, single or clustered, reddish-purple nodules.¹⁰ Histologically, it is characterized by highly vascularized, histiocyterich infiltrates with admixed neutrophils and plasma cells (Figure 3). Capillaries often proliferate in a lobular fashion.¹¹ Atypical cytology with areas of necrosis may mimic angiosarcoma.¹² The pathognomonic feature of BA is the presence of enlarged histiocytes with pink-purplish cytoplasm corresponding to intracytoplasmic aggregates of bacteria, which can be revealed by Warthin-Starry or Grocott-Gomori methenamine-silver staining. Immunohistochemically, proliferative benign capillaries are highlighted by CD34 and CD31, and histiocytes are decorated by CD68.¹² This diagnosis was excluded based on the patient’s history, clinical presentation, and positive staining for CK5 and p63.

Squamoid eccrine ductal carcinoma is an exceedingly rare subtype of eccrine carcinoma that mimics SCC both clinically and histologically.¹³ It most often occurs on the head and neck of elderly patients. This neoplasm can look similar to SCC and its variants, including PSCC. Histologically, squamoid eccrine ductal carcinoma exhibits a biphasic growth pattern.¹⁴ Well-differentiated squamous dysplasia transitions to carcinoma with eccrine duct formation as the tumor percolates deep into the dermis (Figure 4). As a result, superficial skin biopsies often lead to an incorrect diagnosis.¹⁵ Unlike SCC, the risk for locoregional and widespread metastasis is elevated. Identifying ducts in the deep aspect of the tumor is critical, thus immunohistochemical staining for carcinoembryonic antigen and epithelial membrane antigen is paramount for the diagnosis.¹⁵ Pseudoangiomatous SCC will stain negative for carcinoembryonic antigen, as was the case in our patient.

Pseudoepitheliomatous hyperplasia is a benign histologic reaction that can result from trauma, chronic inflammation (ie, pyoderma gangrenosum), tattoo placement, underlying neoplasia or fungal infection, or a spider bite reaction.^14,15 It most commonly is seen as a well-demarcated nodule or plaque associated with scaling or crusting. Papules vary in size from less than 1 cm to several centimeters. Histologically, it is defined by an acanthotic proliferation of the adnexal epithelium and epidermis (Figure 5).^16,17 Irregular strands, cords, and nests of squamoid cells can extend into the dermis.¹⁸ It can closely mimic SCC, but there are a few key differences. Pseudoepitheliomatous hyperplasia will not display atypical mitotic figures or atypical nuclei and will never invade lymphatics or vascular systems.¹⁹ Pseudoepitheliomatous hyperplasia shows identical histology to well-differentiated SCC, and thus clinicopathologic correlation and mindful histologic evaluation are crucial. The presence of an increased influx of neutrophils and histiocytes should prompt for microbial stains or deeper sectioning. A superficial biopsy should be followed by a deep biopsy. In our patient, microorganismal stains were negative.

The Diagnosis: Pseudoangiomatous Squamous Cell Carcinoma

Pseudoangiomatous squamous cell carcinoma (PSCC), a variant of acantholytic squamous cell carcinoma (SCC), is a rare epithelial neoplasm that can mimic angiosarcoma.¹ Clinically, PSCC presents as a white-gray ulcer or nodular pink tumor on sun-exposed areas, typically on the head and neck. Due to its increased potential for metastasis, this variant of SCC is considered particularly aggressive. Histologically, PSCC shows nests of acantholytic atypical keratinocytes arranged in anastomosing arrays that form pseudovascular or pseudoglandular structures.² Acantholytic spaces frequently are filled with erythrocytes. Immunohistochemically, PSCC tumor cells express classic squamous markers such as cytokeratin (CK) 5 and p63 but not vascular markers such as CD31, CD34, and von Willebrand factor.³ In our patient, histopathology of the lesion revealed invasive nests, lobules, and interconnected columns of well-differentiated squamous tumor cells that emanated from the base of the epidermis. The tumor exhibited acantholysis forming ectatic and slitlike spaces, some of which contained erythrocytes. The neoplastic cells, including those lining pseudovascular spaces, positively stained for CK5 (Figure 1A) and nuclear p63 but lacked reactivity to CD31 (Figure 1B) and CD34, corroborating squamous and not vascular differentiation. Current treatment guidelines include Mohs micrographic surgery, excisional surgery, or radiation.⁴ Our patient’s lesion was completely removed by Mohs micrographic surgery. Three months later, there was no evidence of recurrence.

Angiosarcoma is an aggressive neoplasm associated with a poor prognosis and 5-year survival rate of 30% to 40%. The etiology of angiosarcoma still is unclear, but identified risk factors include prior radiation therapy, lymphedema (Stewart-Treves syndrome), and genetic predisposition.⁵ In the skin, angiosarcoma often occurs in the head and neck region, accounting for 60% of cutaneous cases.^5,6 Early in the disease, most patients present with a bruiselike lesion on the scalp or forehead, often delaying the diagnosis.⁶ As the cancer progresses, tissue infiltration, edema, and hemorrhage contribute to the formation of violaceous nodules, which eventually prompt for biopsy. Angiosarcoma spans a broad histologic spectrum depending on the cytology of malignant cells (eg, spindle, small round, epithelioid) and their capacity for vasoformation. Welldifferentiated angiosarcoma shows retiform slitlike spaces in between collagen bundles that are lined by hyperchromatic hobnailing endothelial cells (Figure 2).⁷ Epithelioid angiosarcoma can be mistaken for SCC.⁸ Immunohistochemically, angiosarcoma stains positively for CD31, CD34, ETS-related gene 1, D2-40, and factor VIII.9 In our patient, the neoplasm was negative for vascular markers CD31 and CD34.

Bacillary angiomatosis (BA), caused by Bartonella henselae, is a rare disease that first was identified in HIV patients with diminished CD4+ T-cell counts. In the skin, BA often manifests as centrally ulcerated, single or clustered, reddish-purple nodules.¹⁰ Histologically, it is characterized by highly vascularized, histiocyterich infiltrates with admixed neutrophils and plasma cells (Figure 3). Capillaries often proliferate in a lobular fashion.¹¹ Atypical cytology with areas of necrosis may mimic angiosarcoma.¹² The pathognomonic feature of BA is the presence of enlarged histiocytes with pink-purplish cytoplasm corresponding to intracytoplasmic aggregates of bacteria, which can be revealed by Warthin-Starry or Grocott-Gomori methenamine-silver staining. Immunohistochemically, proliferative benign capillaries are highlighted by CD34 and CD31, and histiocytes are decorated by CD68.¹² This diagnosis was excluded based on the patient’s history, clinical presentation, and positive staining for CK5 and p63.

Squamoid eccrine ductal carcinoma is an exceedingly rare subtype of eccrine carcinoma that mimics SCC both clinically and histologically.¹³ It most often occurs on the head and neck of elderly patients. This neoplasm can look similar to SCC and its variants, including PSCC. Histologically, squamoid eccrine ductal carcinoma exhibits a biphasic growth pattern.¹⁴ Well-differentiated squamous dysplasia transitions to carcinoma with eccrine duct formation as the tumor percolates deep into the dermis (Figure 4). As a result, superficial skin biopsies often lead to an incorrect diagnosis.¹⁵ Unlike SCC, the risk for locoregional and widespread metastasis is elevated. Identifying ducts in the deep aspect of the tumor is critical, thus immunohistochemical staining for carcinoembryonic antigen and epithelial membrane antigen is paramount for the diagnosis.¹⁵ Pseudoangiomatous SCC will stain negative for carcinoembryonic antigen, as was the case in our patient.

Pseudoepitheliomatous hyperplasia is a benign histologic reaction that can result from trauma, chronic inflammation (ie, pyoderma gangrenosum), tattoo placement, underlying neoplasia or fungal infection, or a spider bite reaction.^14,15 It most commonly is seen as a well-demarcated nodule or plaque associated with scaling or crusting. Papules vary in size from less than 1 cm to several centimeters. Histologically, it is defined by an acanthotic proliferation of the adnexal epithelium and epidermis (Figure 5).^16,17 Irregular strands, cords, and nests of squamoid cells can extend into the dermis.¹⁸ It can closely mimic SCC, but there are a few key differences. Pseudoepitheliomatous hyperplasia will not display atypical mitotic figures or atypical nuclei and will never invade lymphatics or vascular systems.¹⁹ Pseudoepitheliomatous hyperplasia shows identical histology to well-differentiated SCC, and thus clinicopathologic correlation and mindful histologic evaluation are crucial. The presence of an increased influx of neutrophils and histiocytes should prompt for microbial stains or deeper sectioning. A superficial biopsy should be followed by a deep biopsy. In our patient, microorganismal stains were negative.

Pemphigus is a group of autoimmune blistering diseases characterized by the development of painful and flaccid blisters on the skin and/or mucous membranes. Pemphigus vulgaris (PV) and pemphigus foliaceus (PF) are 2 major subtypes and can be distinguished by the location of blister formation or the specificity of autoantibodies directed against different desmogleins.^1,2 Although rare, pemphigus is considered a serious and life-threatening condition with a great impact on quality of life (QOL) due to disease symptoms (eg, painful lesions, physical appearance of skin lesions) as well as treatment complications (eg, adverse drug effects, cost of treatment).^3-6 Moreover, the physical and psychological effects can lead to marked functional morbidity and work-related disability during patients’ productive years.⁷ Therefore, affected individuals usually have a remarkably compromised health-related quality of life (HRQOL).⁸ Effective treatments may considerably improve the QOL of patients with pemphigus.⁶

Despite the available treatment options, finding the best regimen for pemphigus remains a challenge. Corticosteroids are assumed to be the main treatment, though they have considerable side effects.^9,10 Adjuvant therapies are used to suppress or modulate immune responses, leading to remission with the least possible need for corticosteroids. Finding an optimal steroid-sparing agent has been the aim of research, and biologic agents seem to be the best option.⁸ Rituximab (RTX), an anti-CD20 monoclonal antibody, has shown great promise in several studies of its clinical efficacy and has become a first-line treatment in new guidelines.^11-14 Rituximab treatment has been associated with notable improvement in physician-assessed outcome measures with a favorable safety profile in patients with pemphigus.^11-15 However, it is important to assess response to treatment from a patient’s perspective through the use of outcome-assessment measures that encompass patient-reported outcomes to reflect the complete patient experience and establish the overall impact of RTX as well as its likelihood of acceptance by patients with pemphigus.

In our study, we compared clinical outcomes and HRQOL through the use of disease-specific measures as well as comprehensive generic health status measures among patients with PV and PF who received RTX treatment 3 months earlier and those who received RTX in the last 2 weeks. The clinical relevance of the patient-reported outcomes is discussed.

MATERIALS AND METHODS

Study Design

We conducted a single-center cross-sectional study of 96 patients with pemphigus aged 18 to 65 years of either sex who were willing to participate in this study. Patients with a confirmed diagnosis of PV or PF who received RTX 3 months earlier or in the last 2 weeks were enrolled in the study. Patients were identified using Dermatry.ir, an archiving software that contains patients’ medical data. Exclusion criteria included lack of sufficient knowledge of the concepts of the questionnaires as well as age younger than 16 years. The study was conducted from October 2019 to April 2020 by the Autoimmune Bullous Disease Research Center at Razi Hospital in Tehran, Iran, which is the main dermatology-specific center and teaching hospital of Iran. The study protocol was approved by the relevant ethics committee.

Patients were categorized into 2 groups: (1) those who received RTX 3 months earlier (3M group); and (2) those who received RTX in the last 2 weeks (R group).

After an explanation of the study to participants, informed written consent was signed by each patient, and their personal data (eg, age, sex, education, marital status, smoking status), as well as clinical data (eg, type of pemphigus, duration of disease, site of onset, prednisolone dosage, presence of Nikolsky sign, anti-DSG1 and anti-DSG3 values, Pemphigus Disease Area Index [PDAI] score, RTX treatment protocol); any known comorbidities such as hypertension, diabetes mellitus, or morbid obesity; and any chronic pulmonary, cardiac, endocrinologic, renal, or hepatic condition, were collected and recorded in a predefined Case Record.

Patient-Reported Outcome Measures

The effect of RTX on QOL in patients with pemphigus was assessed using 2 HRQOL instruments: (1) a general health status indicator, the 36-Item Short Form Survey (SF-36), and (2) a validated, Persian version of a dermatology-specific questionnaire, Dermatology Life Quality Index (DLQI). The questionnaires were completed by each patient or by an assistant if needed.

The SF-36 is a widely used 36-item questionnaire measuring functional health and well-being across 8 domains—mental health, pain, physical function, role emotional, role physical, social functioning, vitality, and general health perception—with scores for each ranging from 0 to 100. The physical component scores (PCSs) and mental component scores (MCSs) were derived from these 8 subscales, each ranging from 0 to 400, with higher scores indicating better health status.⁶

The DLQI, one of the most frequently used QOL measures in dermatology, contains 10 questions, each referring to the prior week and classified in the following 6 subscales: symptoms and feelings, daily activities, leisure, personal relationships, work and school, and treatment.¹⁶ The total score ranges from 0 (no impact) to 30 (very high impact), with a higher score indicating a lower QOL (eTable 1). The minimal clinically important difference (MCD) for the DLQI was considered to be 2- to 5-point changes in prior studies.^17,18 In this study, we used an MCD of a 5-point change or more between study groups.

Moreover, the patient general assessment (PGA) of disease severity was identified using a 3-point scale (1=mild, 2=moderate, 3=severe).

Statistical Analysis

Data were analyzed using SPSS Statistics version 23. P≤.05 was considered significant. Mean and SD were calculated for descriptive data. The t test, Fisher exact test, analysis of variance, multiple regression analysis, and logistic regression analysis were used to identify the relationship between variables.

RESULTS

Patient Characteristics

A total of 96 patients were enrolled in this study. The mean (SD) age of participants was 41.42 (15.1) years (range, 18–58 years). Of 96 patients whose data were included, 55 (57.29%) patients had received RTX 3 months earlier (3M group) and 41 (42.71%) received RTX in the last 2 weeks (R group). A summary of study patient characteristics in each group is provided in eTable 2. There was no significant difference between the 2 groups in terms of age, sex, type of pemphigus, marital status, education, positive Nikolsky sign, smoking status, existence of comorbidities, site of lesions, and RTX treatment protocol. However, a significant difference was found for duration of disease (P=.0124) and mean prednisolone dosage (P=.001) as well as severity of disease measured by PDAI score (P=.003) and anti-DSG1 (P=.003) and anti-DSG3 (P=.021) values.

Patient-Reported Outcomes

Physical and mental component scores are summarized in eTable 3. Generally, SF-36 scores were improved with RTX treatment in all dimensions except for mental health, though these differences were not statistically significant, with the greatest mean improvement in the role physical index (75.45 in the 3M group vs 53.04 in the R group; P=.009). Mean SF-36 PCS and MCS scores were higher in the 3M group vs the R group, though the difference in MCS score did not reach the level of significance (eTable 3).

Mean DLQI scores in the R and 3M groups were 12.31 and 6.96, respectively, indicating a considerable burden on HRQOL in both groups. However, a statistically significant difference between these values was seen that also was clinically meaningful, indicating a significant improvement of QOL in patients receiving RTX 3 months earlier (P=.005)(eTable 3).

The PGA scores indicated that patients in the 3M group were significantly more likely to report less severe disease vs the R group (P=.008)(eTable 3).

Multivariate Analysis—Effect of the patient characteristics and some disease features on indices of QOL was evaluated using the multiple linear regression model. eTable 4 shows the P values of those analyses.

COMMENT

Pemphigus is a chronic disabling disease with notable QOL impairment due to disease burden as well as the need for long-term use of immunosuppressive agents during the disease course. To study the effect of RTX on QOL of patients with pemphigus, we compared 2 sets of patients. Prior studies have shown that clinically significant effects of RTX take 4 to 12 weeks to appear.^19,20 Therefore, we selected patients who received RTX 3 months earlier to measure their HRQOL indices and compare them with patients who had received RTX in the last 2 weeks as a control group to investigate the effect of RTX intrinsically, as this was the focus of this study.

In our study, one of the research tools was the DLQI. Healthy patients typically have an average score of 0.5.²¹ The mean DLQI score of the patients in R group was 12.31, which was similar to prior analysis⁸ and reflects a substantial burden of disease comparable to atopic dermatitis and psoriasis.^21,22 In patients in the 3M group, the mean DLQI score was lower than the R group (6.96 vs 12.31), indicating a significant (P=.005) and clinically meaningful improvement in QOL of patients due to the dramatic therapeutic effect of RTX. However, this score indicated a moderate effect on HRQOL, even in the context of clinical improvement due to RTX treatment, which may reflect that the short duration of treatment in the 3M group was a limitation of this study. Although the 12-week treatment duration was comparable with other studies^19,20 and major differences in objective measures of treatment efficacy were found in PDAI as well as anti-DSG1 and anti-DSG3 values, longer treatment duration may be needed for a more comprehensive assessment of the benefit of RTX on HRQOL indices in patients with pemphigus.

Based on results of the SF-36 questionnaire, PCS and MCS scores were not substantially impaired in the R group considering the fact that a mean score of 50 has been articulated as a normative value for all scales.²³ These data demonstrated the importance of using a dermatologic-specific instrument such as the DLQI instead of a general questionnaire to assess QOL in patients with pemphigus. However, better indices were reported with RTX treatment in the 3 SF-36 domains—role physical (P=.009), role emotional (P=.03), and general health perception (P=.03)—with the role physical showing the greatest magnitude of mean change (75.45 in the 3M group vs 53.04 in the R group). Notably, PCS was impaired to a greater extent than MCS in patients in the R group and showed a greater magnitude of improvement after 3 months of treatment. These results could be explained by the fact that MCS can be largely changed in diseases with a direct effect on the central nervous system.²³

Our results also revealed that the dose of corticosteroid correlated to HRQOL of patients with pemphigus who recently received RTX therapy. Indeed, it is more likely that patients on lower-dose prednisolone have a higher QOL, especially on physical function and social function dimensions of SF-36. This finding is highly expectable by less severe disease due to RTX treatment and also lower potential dose-dependent adverse effects of long-term steroid therapy.

One of the most striking findings of this study was the correlation of location of lesions to QOL indices. We found that the mucocutaneous phenotype was significantly correlated to greater improvement in role emotional, role physical, and social functioning scores due to RTX treatment compared with cutaneous or mucosal types (P=.02, P=.025, and P=.017, respectively). Although mucosal involvement of the disease can be the most burdensome feature because of its large impact on essential activities such as eating and speaking, cutaneous lesions with unpleasant appearance and undesirable symptoms may have a similar impact on QOL. Therefore, having both mucosal and cutaneous lesions causes a worsened QOL and decreased treatment efficacy vs having only one area involved. This may explain the greater improvement in some QOL indices with RTX treatment.

Limitations—Given the cross-sectional design of this study in which patients were observed at a single time point during their treatment course, it is not possible to establish a clear cause-effect relationship between variables. Moreover, we did not evaluate the impact of RTX or prednisolone adverse effects on QOL. Therefore, further prospective studies with longer treatment durations may help to validate our findings. In addition, MCDs for DLQI and SF-36 in pemphigus need to be determined and validated in future studies.

CONCLUSION

The results of our study demonstrated that patients with pemphigus may benefit from taking RTX, not only in terms of clinical improvement of their disease measured by objective indices such as PDAI and anti-DSG1 and anti-DSG3 values but also in several domains that are important to patients, including physical and mental health status (SF-36), HRQOL (DLQI), and overall disease severity (PGA). Rituximab administration in patients with pemphigus can lead to rapid and significant improvement in HRQOL as well as patient- and physician-assessed measures. Its favorable safety profile along with its impact on patients’ daily lives and mental health makes RTX a suitable treatment option for patients with pemphigus. Moreover, we recommend taking QOL indices into account while evaluating the efficacy of new medications to improve our insight into the patient experience and provide better patient adherence to treatment, which is an important issue for optimal control of chronic disorders.

Pemphigus is a group of autoimmune blistering diseases characterized by the development of painful and flaccid blisters on the skin and/or mucous membranes. Pemphigus vulgaris (PV) and pemphigus foliaceus (PF) are 2 major subtypes and can be distinguished by the location of blister formation or the specificity of autoantibodies directed against different desmogleins.^1,2 Although rare, pemphigus is considered a serious and life-threatening condition with a great impact on quality of life (QOL) due to disease symptoms (eg, painful lesions, physical appearance of skin lesions) as well as treatment complications (eg, adverse drug effects, cost of treatment).^3-6 Moreover, the physical and psychological effects can lead to marked functional morbidity and work-related disability during patients’ productive years.⁷ Therefore, affected individuals usually have a remarkably compromised health-related quality of life (HRQOL).⁸ Effective treatments may considerably improve the QOL of patients with pemphigus.⁶

Despite the available treatment options, finding the best regimen for pemphigus remains a challenge. Corticosteroids are assumed to be the main treatment, though they have considerable side effects.^9,10 Adjuvant therapies are used to suppress or modulate immune responses, leading to remission with the least possible need for corticosteroids. Finding an optimal steroid-sparing agent has been the aim of research, and biologic agents seem to be the best option.⁸ Rituximab (RTX), an anti-CD20 monoclonal antibody, has shown great promise in several studies of its clinical efficacy and has become a first-line treatment in new guidelines.^11-14 Rituximab treatment has been associated with notable improvement in physician-assessed outcome measures with a favorable safety profile in patients with pemphigus.^11-15 However, it is important to assess response to treatment from a patient’s perspective through the use of outcome-assessment measures that encompass patient-reported outcomes to reflect the complete patient experience and establish the overall impact of RTX as well as its likelihood of acceptance by patients with pemphigus.

In our study, we compared clinical outcomes and HRQOL through the use of disease-specific measures as well as comprehensive generic health status measures among patients with PV and PF who received RTX treatment 3 months earlier and those who received RTX in the last 2 weeks. The clinical relevance of the patient-reported outcomes is discussed.

MATERIALS AND METHODS

Study Design

We conducted a single-center cross-sectional study of 96 patients with pemphigus aged 18 to 65 years of either sex who were willing to participate in this study. Patients with a confirmed diagnosis of PV or PF who received RTX 3 months earlier or in the last 2 weeks were enrolled in the study. Patients were identified using Dermatry.ir, an archiving software that contains patients’ medical data. Exclusion criteria included lack of sufficient knowledge of the concepts of the questionnaires as well as age younger than 16 years. The study was conducted from October 2019 to April 2020 by the Autoimmune Bullous Disease Research Center at Razi Hospital in Tehran, Iran, which is the main dermatology-specific center and teaching hospital of Iran. The study protocol was approved by the relevant ethics committee.

Patients were categorized into 2 groups: (1) those who received RTX 3 months earlier (3M group); and (2) those who received RTX in the last 2 weeks (R group).

After an explanation of the study to participants, informed written consent was signed by each patient, and their personal data (eg, age, sex, education, marital status, smoking status), as well as clinical data (eg, type of pemphigus, duration of disease, site of onset, prednisolone dosage, presence of Nikolsky sign, anti-DSG1 and anti-DSG3 values, Pemphigus Disease Area Index [PDAI] score, RTX treatment protocol); any known comorbidities such as hypertension, diabetes mellitus, or morbid obesity; and any chronic pulmonary, cardiac, endocrinologic, renal, or hepatic condition, were collected and recorded in a predefined Case Record.

Patient-Reported Outcome Measures

The effect of RTX on QOL in patients with pemphigus was assessed using 2 HRQOL instruments: (1) a general health status indicator, the 36-Item Short Form Survey (SF-36), and (2) a validated, Persian version of a dermatology-specific questionnaire, Dermatology Life Quality Index (DLQI). The questionnaires were completed by each patient or by an assistant if needed.

The SF-36 is a widely used 36-item questionnaire measuring functional health and well-being across 8 domains—mental health, pain, physical function, role emotional, role physical, social functioning, vitality, and general health perception—with scores for each ranging from 0 to 100. The physical component scores (PCSs) and mental component scores (MCSs) were derived from these 8 subscales, each ranging from 0 to 400, with higher scores indicating better health status.⁶

The DLQI, one of the most frequently used QOL measures in dermatology, contains 10 questions, each referring to the prior week and classified in the following 6 subscales: symptoms and feelings, daily activities, leisure, personal relationships, work and school, and treatment.¹⁶ The total score ranges from 0 (no impact) to 30 (very high impact), with a higher score indicating a lower QOL (eTable 1). The minimal clinically important difference (MCD) for the DLQI was considered to be 2- to 5-point changes in prior studies.^17,18 In this study, we used an MCD of a 5-point change or more between study groups.

Moreover, the patient general assessment (PGA) of disease severity was identified using a 3-point scale (1=mild, 2=moderate, 3=severe).

Statistical Analysis

Data were analyzed using SPSS Statistics version 23. P≤.05 was considered significant. Mean and SD were calculated for descriptive data. The t test, Fisher exact test, analysis of variance, multiple regression analysis, and logistic regression analysis were used to identify the relationship between variables.

RESULTS

Patient Characteristics

A total of 96 patients were enrolled in this study. The mean (SD) age of participants was 41.42 (15.1) years (range, 18–58 years). Of 96 patients whose data were included, 55 (57.29%) patients had received RTX 3 months earlier (3M group) and 41 (42.71%) received RTX in the last 2 weeks (R group). A summary of study patient characteristics in each group is provided in eTable 2. There was no significant difference between the 2 groups in terms of age, sex, type of pemphigus, marital status, education, positive Nikolsky sign, smoking status, existence of comorbidities, site of lesions, and RTX treatment protocol. However, a significant difference was found for duration of disease (P=.0124) and mean prednisolone dosage (P=.001) as well as severity of disease measured by PDAI score (P=.003) and anti-DSG1 (P=.003) and anti-DSG3 (P=.021) values.

Patient-Reported Outcomes

Physical and mental component scores are summarized in eTable 3. Generally, SF-36 scores were improved with RTX treatment in all dimensions except for mental health, though these differences were not statistically significant, with the greatest mean improvement in the role physical index (75.45 in the 3M group vs 53.04 in the R group; P=.009). Mean SF-36 PCS and MCS scores were higher in the 3M group vs the R group, though the difference in MCS score did not reach the level of significance (eTable 3).

Mean DLQI scores in the R and 3M groups were 12.31 and 6.96, respectively, indicating a considerable burden on HRQOL in both groups. However, a statistically significant difference between these values was seen that also was clinically meaningful, indicating a significant improvement of QOL in patients receiving RTX 3 months earlier (P=.005)(eTable 3).

The PGA scores indicated that patients in the 3M group were significantly more likely to report less severe disease vs the R group (P=.008)(eTable 3).

Multivariate Analysis—Effect of the patient characteristics and some disease features on indices of QOL was evaluated using the multiple linear regression model. eTable 4 shows the P values of those analyses.

COMMENT

Pemphigus is a chronic disabling disease with notable QOL impairment due to disease burden as well as the need for long-term use of immunosuppressive agents during the disease course. To study the effect of RTX on QOL of patients with pemphigus, we compared 2 sets of patients. Prior studies have shown that clinically significant effects of RTX take 4 to 12 weeks to appear.^19,20 Therefore, we selected patients who received RTX 3 months earlier to measure their HRQOL indices and compare them with patients who had received RTX in the last 2 weeks as a control group to investigate the effect of RTX intrinsically, as this was the focus of this study.

In our study, one of the research tools was the DLQI. Healthy patients typically have an average score of 0.5.²¹ The mean DLQI score of the patients in R group was 12.31, which was similar to prior analysis⁸ and reflects a substantial burden of disease comparable to atopic dermatitis and psoriasis.^21,22 In patients in the 3M group, the mean DLQI score was lower than the R group (6.96 vs 12.31), indicating a significant (P=.005) and clinically meaningful improvement in QOL of patients due to the dramatic therapeutic effect of RTX. However, this score indicated a moderate effect on HRQOL, even in the context of clinical improvement due to RTX treatment, which may reflect that the short duration of treatment in the 3M group was a limitation of this study. Although the 12-week treatment duration was comparable with other studies^19,20 and major differences in objective measures of treatment efficacy were found in PDAI as well as anti-DSG1 and anti-DSG3 values, longer treatment duration may be needed for a more comprehensive assessment of the benefit of RTX on HRQOL indices in patients with pemphigus.

Based on results of the SF-36 questionnaire, PCS and MCS scores were not substantially impaired in the R group considering the fact that a mean score of 50 has been articulated as a normative value for all scales.²³ These data demonstrated the importance of using a dermatologic-specific instrument such as the DLQI instead of a general questionnaire to assess QOL in patients with pemphigus. However, better indices were reported with RTX treatment in the 3 SF-36 domains—role physical (P=.009), role emotional (P=.03), and general health perception (P=.03)—with the role physical showing the greatest magnitude of mean change (75.45 in the 3M group vs 53.04 in the R group). Notably, PCS was impaired to a greater extent than MCS in patients in the R group and showed a greater magnitude of improvement after 3 months of treatment. These results could be explained by the fact that MCS can be largely changed in diseases with a direct effect on the central nervous system.²³

Our results also revealed that the dose of corticosteroid correlated to HRQOL of patients with pemphigus who recently received RTX therapy. Indeed, it is more likely that patients on lower-dose prednisolone have a higher QOL, especially on physical function and social function dimensions of SF-36. This finding is highly expectable by less severe disease due to RTX treatment and also lower potential dose-dependent adverse effects of long-term steroid therapy.

One of the most striking findings of this study was the correlation of location of lesions to QOL indices. We found that the mucocutaneous phenotype was significantly correlated to greater improvement in role emotional, role physical, and social functioning scores due to RTX treatment compared with cutaneous or mucosal types (P=.02, P=.025, and P=.017, respectively). Although mucosal involvement of the disease can be the most burdensome feature because of its large impact on essential activities such as eating and speaking, cutaneous lesions with unpleasant appearance and undesirable symptoms may have a similar impact on QOL. Therefore, having both mucosal and cutaneous lesions causes a worsened QOL and decreased treatment efficacy vs having only one area involved. This may explain the greater improvement in some QOL indices with RTX treatment.

Limitations—Given the cross-sectional design of this study in which patients were observed at a single time point during their treatment course, it is not possible to establish a clear cause-effect relationship between variables. Moreover, we did not evaluate the impact of RTX or prednisolone adverse effects on QOL. Therefore, further prospective studies with longer treatment durations may help to validate our findings. In addition, MCDs for DLQI and SF-36 in pemphigus need to be determined and validated in future studies.

CONCLUSION

The results of our study demonstrated that patients with pemphigus may benefit from taking RTX, not only in terms of clinical improvement of their disease measured by objective indices such as PDAI and anti-DSG1 and anti-DSG3 values but also in several domains that are important to patients, including physical and mental health status (SF-36), HRQOL (DLQI), and overall disease severity (PGA). Rituximab administration in patients with pemphigus can lead to rapid and significant improvement in HRQOL as well as patient- and physician-assessed measures. Its favorable safety profile along with its impact on patients’ daily lives and mental health makes RTX a suitable treatment option for patients with pemphigus. Moreover, we recommend taking QOL indices into account while evaluating the efficacy of new medications to improve our insight into the patient experience and provide better patient adherence to treatment, which is an important issue for optimal control of chronic disorders.

Pemphigus is a group of autoimmune blistering diseases characterized by the development of painful and flaccid blisters on the skin and/or mucous membranes. Pemphigus vulgaris (PV) and pemphigus foliaceus (PF) are 2 major subtypes and can be distinguished by the location of blister formation or the specificity of autoantibodies directed against different desmogleins.^1,2 Although rare, pemphigus is considered a serious and life-threatening condition with a great impact on quality of life (QOL) due to disease symptoms (eg, painful lesions, physical appearance of skin lesions) as well as treatment complications (eg, adverse drug effects, cost of treatment).^3-6 Moreover, the physical and psychological effects can lead to marked functional morbidity and work-related disability during patients’ productive years.⁷ Therefore, affected individuals usually have a remarkably compromised health-related quality of life (HRQOL).⁸ Effective treatments may considerably improve the QOL of patients with pemphigus.⁶

Despite the available treatment options, finding the best regimen for pemphigus remains a challenge. Corticosteroids are assumed to be the main treatment, though they have considerable side effects.^9,10 Adjuvant therapies are used to suppress or modulate immune responses, leading to remission with the least possible need for corticosteroids. Finding an optimal steroid-sparing agent has been the aim of research, and biologic agents seem to be the best option.⁸ Rituximab (RTX), an anti-CD20 monoclonal antibody, has shown great promise in several studies of its clinical efficacy and has become a first-line treatment in new guidelines.^11-14 Rituximab treatment has been associated with notable improvement in physician-assessed outcome measures with a favorable safety profile in patients with pemphigus.^11-15 However, it is important to assess response to treatment from a patient’s perspective through the use of outcome-assessment measures that encompass patient-reported outcomes to reflect the complete patient experience and establish the overall impact of RTX as well as its likelihood of acceptance by patients with pemphigus.

In our study, we compared clinical outcomes and HRQOL through the use of disease-specific measures as well as comprehensive generic health status measures among patients with PV and PF who received RTX treatment 3 months earlier and those who received RTX in the last 2 weeks. The clinical relevance of the patient-reported outcomes is discussed.

MATERIALS AND METHODS

Study Design

We conducted a single-center cross-sectional study of 96 patients with pemphigus aged 18 to 65 years of either sex who were willing to participate in this study. Patients with a confirmed diagnosis of PV or PF who received RTX 3 months earlier or in the last 2 weeks were enrolled in the study. Patients were identified using Dermatry.ir, an archiving software that contains patients’ medical data. Exclusion criteria included lack of sufficient knowledge of the concepts of the questionnaires as well as age younger than 16 years. The study was conducted from October 2019 to April 2020 by the Autoimmune Bullous Disease Research Center at Razi Hospital in Tehran, Iran, which is the main dermatology-specific center and teaching hospital of Iran. The study protocol was approved by the relevant ethics committee.

Patients were categorized into 2 groups: (1) those who received RTX 3 months earlier (3M group); and (2) those who received RTX in the last 2 weeks (R group).

After an explanation of the study to participants, informed written consent was signed by each patient, and their personal data (eg, age, sex, education, marital status, smoking status), as well as clinical data (eg, type of pemphigus, duration of disease, site of onset, prednisolone dosage, presence of Nikolsky sign, anti-DSG1 and anti-DSG3 values, Pemphigus Disease Area Index [PDAI] score, RTX treatment protocol); any known comorbidities such as hypertension, diabetes mellitus, or morbid obesity; and any chronic pulmonary, cardiac, endocrinologic, renal, or hepatic condition, were collected and recorded in a predefined Case Record.

Patient-Reported Outcome Measures

The effect of RTX on QOL in patients with pemphigus was assessed using 2 HRQOL instruments: (1) a general health status indicator, the 36-Item Short Form Survey (SF-36), and (2) a validated, Persian version of a dermatology-specific questionnaire, Dermatology Life Quality Index (DLQI). The questionnaires were completed by each patient or by an assistant if needed.

The SF-36 is a widely used 36-item questionnaire measuring functional health and well-being across 8 domains—mental health, pain, physical function, role emotional, role physical, social functioning, vitality, and general health perception—with scores for each ranging from 0 to 100. The physical component scores (PCSs) and mental component scores (MCSs) were derived from these 8 subscales, each ranging from 0 to 400, with higher scores indicating better health status.⁶

The DLQI, one of the most frequently used QOL measures in dermatology, contains 10 questions, each referring to the prior week and classified in the following 6 subscales: symptoms and feelings, daily activities, leisure, personal relationships, work and school, and treatment.¹⁶ The total score ranges from 0 (no impact) to 30 (very high impact), with a higher score indicating a lower QOL (eTable 1). The minimal clinically important difference (MCD) for the DLQI was considered to be 2- to 5-point changes in prior studies.^17,18 In this study, we used an MCD of a 5-point change or more between study groups.

Moreover, the patient general assessment (PGA) of disease severity was identified using a 3-point scale (1=mild, 2=moderate, 3=severe).

Statistical Analysis

Data were analyzed using SPSS Statistics version 23. P≤.05 was considered significant. Mean and SD were calculated for descriptive data. The t test, Fisher exact test, analysis of variance, multiple regression analysis, and logistic regression analysis were used to identify the relationship between variables.

RESULTS

Patient Characteristics

A total of 96 patients were enrolled in this study. The mean (SD) age of participants was 41.42 (15.1) years (range, 18–58 years). Of 96 patients whose data were included, 55 (57.29%) patients had received RTX 3 months earlier (3M group) and 41 (42.71%) received RTX in the last 2 weeks (R group). A summary of study patient characteristics in each group is provided in eTable 2. There was no significant difference between the 2 groups in terms of age, sex, type of pemphigus, marital status, education, positive Nikolsky sign, smoking status, existence of comorbidities, site of lesions, and RTX treatment protocol. However, a significant difference was found for duration of disease (P=.0124) and mean prednisolone dosage (P=.001) as well as severity of disease measured by PDAI score (P=.003) and anti-DSG1 (P=.003) and anti-DSG3 (P=.021) values.

Patient-Reported Outcomes

Physical and mental component scores are summarized in eTable 3. Generally, SF-36 scores were improved with RTX treatment in all dimensions except for mental health, though these differences were not statistically significant, with the greatest mean improvement in the role physical index (75.45 in the 3M group vs 53.04 in the R group; P=.009). Mean SF-36 PCS and MCS scores were higher in the 3M group vs the R group, though the difference in MCS score did not reach the level of significance (eTable 3).

Mean DLQI scores in the R and 3M groups were 12.31 and 6.96, respectively, indicating a considerable burden on HRQOL in both groups. However, a statistically significant difference between these values was seen that also was clinically meaningful, indicating a significant improvement of QOL in patients receiving RTX 3 months earlier (P=.005)(eTable 3).

The PGA scores indicated that patients in the 3M group were significantly more likely to report less severe disease vs the R group (P=.008)(eTable 3).

Multivariate Analysis—Effect of the patient characteristics and some disease features on indices of QOL was evaluated using the multiple linear regression model. eTable 4 shows the P values of those analyses.

COMMENT

Pemphigus is a chronic disabling disease with notable QOL impairment due to disease burden as well as the need for long-term use of immunosuppressive agents during the disease course. To study the effect of RTX on QOL of patients with pemphigus, we compared 2 sets of patients. Prior studies have shown that clinically significant effects of RTX take 4 to 12 weeks to appear.^19,20 Therefore, we selected patients who received RTX 3 months earlier to measure their HRQOL indices and compare them with patients who had received RTX in the last 2 weeks as a control group to investigate the effect of RTX intrinsically, as this was the focus of this study.

In our study, one of the research tools was the DLQI. Healthy patients typically have an average score of 0.5.²¹ The mean DLQI score of the patients in R group was 12.31, which was similar to prior analysis⁸ and reflects a substantial burden of disease comparable to atopic dermatitis and psoriasis.^21,22 In patients in the 3M group, the mean DLQI score was lower than the R group (6.96 vs 12.31), indicating a significant (P=.005) and clinically meaningful improvement in QOL of patients due to the dramatic therapeutic effect of RTX. However, this score indicated a moderate effect on HRQOL, even in the context of clinical improvement due to RTX treatment, which may reflect that the short duration of treatment in the 3M group was a limitation of this study. Although the 12-week treatment duration was comparable with other studies^19,20 and major differences in objective measures of treatment efficacy were found in PDAI as well as anti-DSG1 and anti-DSG3 values, longer treatment duration may be needed for a more comprehensive assessment of the benefit of RTX on HRQOL indices in patients with pemphigus.

Based on results of the SF-36 questionnaire, PCS and MCS scores were not substantially impaired in the R group considering the fact that a mean score of 50 has been articulated as a normative value for all scales.²³ These data demonstrated the importance of using a dermatologic-specific instrument such as the DLQI instead of a general questionnaire to assess QOL in patients with pemphigus. However, better indices were reported with RTX treatment in the 3 SF-36 domains—role physical (P=.009), role emotional (P=.03), and general health perception (P=.03)—with the role physical showing the greatest magnitude of mean change (75.45 in the 3M group vs 53.04 in the R group). Notably, PCS was impaired to a greater extent than MCS in patients in the R group and showed a greater magnitude of improvement after 3 months of treatment. These results could be explained by the fact that MCS can be largely changed in diseases with a direct effect on the central nervous system.²³

Our results also revealed that the dose of corticosteroid correlated to HRQOL of patients with pemphigus who recently received RTX therapy. Indeed, it is more likely that patients on lower-dose prednisolone have a higher QOL, especially on physical function and social function dimensions of SF-36. This finding is highly expectable by less severe disease due to RTX treatment and also lower potential dose-dependent adverse effects of long-term steroid therapy.

One of the most striking findings of this study was the correlation of location of lesions to QOL indices. We found that the mucocutaneous phenotype was significantly correlated to greater improvement in role emotional, role physical, and social functioning scores due to RTX treatment compared with cutaneous or mucosal types (P=.02, P=.025, and P=.017, respectively). Although mucosal involvement of the disease can be the most burdensome feature because of its large impact on essential activities such as eating and speaking, cutaneous lesions with unpleasant appearance and undesirable symptoms may have a similar impact on QOL. Therefore, having both mucosal and cutaneous lesions causes a worsened QOL and decreased treatment efficacy vs having only one area involved. This may explain the greater improvement in some QOL indices with RTX treatment.

Limitations—Given the cross-sectional design of this study in which patients were observed at a single time point during their treatment course, it is not possible to establish a clear cause-effect relationship between variables. Moreover, we did not evaluate the impact of RTX or prednisolone adverse effects on QOL. Therefore, further prospective studies with longer treatment durations may help to validate our findings. In addition, MCDs for DLQI and SF-36 in pemphigus need to be determined and validated in future studies.

CONCLUSION

The results of our study demonstrated that patients with pemphigus may benefit from taking RTX, not only in terms of clinical improvement of their disease measured by objective indices such as PDAI and anti-DSG1 and anti-DSG3 values but also in several domains that are important to patients, including physical and mental health status (SF-36), HRQOL (DLQI), and overall disease severity (PGA). Rituximab administration in patients with pemphigus can lead to rapid and significant improvement in HRQOL as well as patient- and physician-assessed measures. Its favorable safety profile along with its impact on patients’ daily lives and mental health makes RTX a suitable treatment option for patients with pemphigus. Moreover, we recommend taking QOL indices into account while evaluating the efficacy of new medications to improve our insight into the patient experience and provide better patient adherence to treatment, which is an important issue for optimal control of chronic disorders.

Hereditary alpha tryptasemia (HaT), an autosomal-dominant disorder of tryptase overproduction, was first described in 2014 by Lyons et al.¹ It has been associated with multiple dermatologic, allergic, gastrointestinal (GI) tract, neuropsychiatric, respiratory, autonomic, and connective tissue abnormalities. These multisystem concerns may include cutaneous flushing, chronic pruritus, urticaria, GI tract symptoms, arthralgia, and autonomic dysfunction.² The diverse symptoms and the recent discovery of HaT make recognition of this disorder challenging. Currently, it also is believed that HaT is associated with an elevated risk for anaphylaxis and is a biomarker for severe symptoms in disorders with increased mast cell burden such as mastocytosis.^3-5

Given the potential cutaneous manifestations and the fact that dermatologic symptoms may be the initial presentation of HaT, awareness and recognition of this condition by dermatologists are essential for diagnosis and treatment. This review summarizes the cutaneous presentations consistent with HaT and discusses various conditions that share overlapping dermatologic symptoms with HaT.

Background on HaT

Mast cells are known to secrete several vasoactive mediators including tryptase and histamine when activated by foreign substances, similar to IgE-mediated hypersensitivity reactions. In their baseline state, mast cells continuously secrete immature forms of tryptases called protryptases.⁶ These protryptases come in 2 forms: α and β. Although mature tryptase is acutely elevatedin anaphylaxis, persistently elevated total serum tryptase levels frequently are regarded as indicative of a systemic mast cell disorder such as systemic mastocytosis (SM).³ Despite the wide-ranging phenotype of HaT, all individuals with the disorder have an elevated basal serum tryptase level (>8 ng/mL). Hereditary alpha tryptasemia has been identified as another possible cause of persistently elevated levels.^2,6

Genetics and Epidemiology of HaT—The humantryptase locus at chromosome 16p13.3 is composed of 4 paralog genes: TPSG1, TPSB2, TPSAB1, and TPSD1.⁴ Only TPSAB1 encodes for α-tryptase, while both TPSB2 and TPSAB1 encode for β-tryptase.⁴ Hereditary alpha tryptasemia is an autosomal-dominant disorder resulting from a copy number increase in the α-tryptase encoding sequence within the TPSAB1 gene. Despite the wide-ranging phenotype of HaT, all individuals identified with the disorder have a basal serum tryptase level greater than 8 ng/mL, with mean (SD) levels of 15 (5) ng/mL and 24 (6) ng/mL with gene duplication and triplication, respectively (reference range, 0–11.4 ng/mL).^2,6 Hereditary alpha tryptasemia likely is common and largely undiagnosed, with a recently estimated prevalence of 5% in the United Kingdom⁷ and 5.6% in a cohort of 125 individuals from Italy, Slovenia, and the United States.⁵

Implications of Increased α-tryptase Levels—After an inciting stimulus, the active portions of α-protryptase and β-protryptase are secreted as tetramers by activated mast cells via degranulation. In vitro, β-tryptase homotetramers have been found to play a role in anaphylaxis, while α-homotetramers are nearly inactive.^8,9 Recently, however, it has been discovered that α2β2 tetramers also can form and do so in a higher ratio in individuals with increased α-tryptase–encoding gene copies, such as those with HaT.⁸ These heterotetramers exhibit unique properties compared with the homotetramers and may stimulate epidermal growth factor–like module-containing mucinlike hormone receptor 2 and protease-activated receptor 2 (PAR2). Epidermal growth factor–like module-containing mucinlike hormone receptor 2 activation likely contributes to vibratory urticaria in patients, while activation of PAR2 may have a range of clinical effects, including worsening asthma, inflammatory bowel disease, pruritus, and the exacerbation of dermal inflammation and hyperalgesia.^8,10 Thus, α- and β-tryptase tetramers can be considered mediators that may influence the severity of disorders in which mast cells are naturally prevalent and likely contribute to the phenotype of those with HaT.⁷ Furthermore, these characteristics have been shown to potentially increase in severity with increasing tryptase levels and with increased TPSAB1 duplications.^1,2 In contrast, more than 25% of the population is deficient in α-tryptase without known deleterious effects.⁵

Cutaneous Manifestations of HaT

A case series reported by Lyons et al¹ in 2014 detailed persistent elevated basal serum tryptase levels in 9 families with an autosomal-dominant pattern of inheritance. In this cohort, 31 of 33 (94%) affected individuals had a history of atopic dermatitis (AD), and 26 of 33 (79%) affected individuals reported symptoms consistent with mast cell degranulation, including urticaria; flushing; and/or crampy abdominal pain unprovoked or triggered by heat, exercise, vibration, stress, certain foods, or minor physical stimulation.¹ A later report by Lyons et al² in 2016 identified the TPSAB1 α-tryptase–encoding sequence copy number increase as the causative entity for HaT by examining a group of 96 patients from 35 families with frequent recurrent cutaneous flushing and pruritus, sometimes associated with urticaria and sleep disruption. Flushing and pruritus were found in 45% (33/73) of those with a TPSAB1 duplication and 80% (12/15) of those with a triplication (P=.022), suggesting a gene dose effect regarding α-tryptase encoding sequence copy number and these symptoms.²

A 2019 study further explored the clinical finding of urticaria in patients with HaT by specifically examining if vibration-induced urticaria was affected by TPSAB1 gene dosage.⁸ A cohort of 56 volunteers—35 healthy and 21 with HaT—underwent tryptase genotyping and cutaneous vibratory challenge. The presence of TPSAB1 was significantly correlated with induction of vibration-induced urticaria (P<.01), as the severity and prevalence of the urticarial response increased along with α- and β-tryptase gene ratios.⁸

Urticaria and angioedema also were seen in 51% (36/70) of patients in a cohort of HaT patients in the United Kingdom, in which 41% (29/70) also had skin flushing. In contrast to prior studies, these manifestations were not more common in patients with gene triplications or quintuplications than those with duplications.⁷ In another recent retrospective evaluation conducted at Brigham and Women’s Hospital (Boston, Massachusetts)(N=101), 80% of patients aged 4 to 85 years with confirmed diagnoses of HaT had skin manifestations such as urticaria, flushing, and pruritus.⁴

HaT and Mast Cell Activation Syndrome—In 2019, a Mast Cell Disorders Committee Work Group Report outlined recommendations for diagnosing and treating primary mast cell activation syndrome (MCAS), a disorder in which mast cells seem to be more easily activated. Mast cell activation syndrome is defined as a primary clinical condition in which there are episodic signs and symptoms of systemic anaphylaxis (Table) concurrently affecting at least 2 organ systems, resulting from secreted mast cell mediators.^9,11 The 2019 report also touched on clinical criteria that lack precision for diagnosing MCAS yet are in use, including dermographism and several types of rashes.⁹ Episode triggers frequent in MCAS include hot water, alcohol, stress, exercise, infection, hormonal changes, and physical stimuli.

Hereditary alpha tryptasemia has been suggested to be a risk factor for MCAS, which also can be associated with SM and clonal MCAS.⁹ Patients with MCAS should be tested for increased α-tryptase gene copy number given the overlap in symptoms, the likely predisposition of those with HaT to develop MCAS, and the fact that these patients could be at an increased risk for anaphylaxis.^4,7,9,11 However, the clinical phenotype for HaT includes allergic disorders affecting the skin as well as neuropsychiatric and connective tissue abnormalities that are distinctive from MCAS. Although HaT may be considered a heritable risk factor for MCAS, MCAS is only 1 potential phenotype associated with HaT.⁹

Implications of HaT

Hereditary alpha tryptasemia should be considered in all patients with basal tryptase levels greater than 8 ng/mL. Cutaneous symptoms are among the most common presentations for individuals with HaT and can include AD, chronic or episodic urticaria, pruritus, flushing, and angioedema. However, HaT is unique because of the coupling of these common dermatologic findings with other abnormalities, including abdominal pain and diarrhea, hypermobile joints, and autonomic dysfunction. Patients with HaT also may manifest psychiatric concerns of anxiety, depression, and chronic pain, all of which have been linked to this disorder.

It is unclear in HaT if the presence of extra-allelic copies of tryptase in an individual is directly pathogenic. The effects of increased basal tryptase and α2β2 tetramers have been shown to likely be responsible for some of the clinical features in these individuals but also may magnify other individual underlying disease(s) or diathesis in which mast cells are naturally abundant.⁸ In the skin, this increased mast cell activation and subsequent histamine release frequently are visible as dermatographia and urticaria. However, mast cell numbers also are known to be increased in both psoriatic and AD skin lesions,¹² thus severe presentation of these diseases in conjunction with the other symptoms associated with mast cell activation should prompt suspicion for HaT.

Effects of HaT on Other Cutaneous Disease—Given the increase of mast cells in AD skin lesions and fact that 94% of patients in the 2014 Lyons et al¹ study cited a history of AD, HaT may be a risk factor in the development of AD. Interestingly, in addition to the increased mast cells in AD lesions, PAR2+ nerve fibers also are increased in AD lesions and have been implicated in the nonhistaminergic pruritus experienced by patients with AD.¹² Thus, given the proposed propensity for α2β2 tetramers to activate PAR2, it is possible this mechanism may contribute to severe pruritus in individuals with AD and concurrent HaT, as those with HaT express increased α2β2 tetramers. However, no study to date has directly compared AD symptoms in patients with concurrent HaT vs patients without it. Further research is needed on how HaT impacts other allergic and inflammatory skin diseases such as AD and psoriasis, but one may reasonably consider HaT when treating chronic inflammatory skin diseases refractory to typical interventions and/or severe presentations. Although HaT is an autosomal-dominant disorder, it is not detected by standard whole exome sequencing or microarrays. A commercial test is available, utilizing a buccal swab to test for TPSAB1 copy number.

HaT and Mast Cell Disorders—When evaluating someone with suspected HaT, it is important to screen for other symptoms of mast cell activation. For instance, in the GI tract increased mast cell activation results in activation of motor neurons and nociceptors and increases secretion and peristalsis with consequent bloating, abdominal pain, and diarrhea.¹⁰ Likewise, tryptase also has neuromodulatory effects that amplify the perception of pain and are likely responsible for the feelings of hyperalgesia reported in patients with HaT.¹³

There is substantial overlap in the clinical pictures of HaT and MCAS, and HaT is considered a heritable risk factor for MCAS. Consequently, any patient undergoing workup for MCAS also should be tested for HaT. Although HaT is associated with consistently elevated tryptase, MCAS is episodic in nature, and an increase in tryptase levels of at least 20% plus 2 ng/mL from baseline only in the presence of other symptoms reflective of mast cell activation (Table) is a prerequisite for diagnosis.⁹ Chronic signs and symptoms of atopy, chronic urticaria, and severe asthma are not indicative of MCAS but are frequently seen in HaT.

Another cause of persistently elevated tryptase levels is SM. Systemic mastocytosis is defined by aberrant clonal mast cell expansion and systemic involvement¹¹ and can cause persistent symptoms, unlike MCAS alone. However, SM also can be associated with MCAS.⁹ Notably, a baseline serum tryptase level greater than 20 ng/mL—much higher than the threshold of greater than 8 ng/mL for suspicion of HaT—is seen in 75% of SM cases and is part of the minor diagnostic criteria for the disease.^9,11 However, the 2016 study identifying increased TPSAB1 α-tryptase–encoding sequences as the causative entity for HaT by Lyons et al² found the average (SD) basal serum tryptase level in individuals with α-tryptase–encoding sequence duplications to be 15 (5) ng/mL and 24 (6) ng/mL in those with triplications. Thus, there likely is no threshold for elevated baseline tryptase levels that would indicate SM over HaT as a more likely diagnosis. However, SM will present with new persistently elevated tryptase levels, whereas the elevation in HaT is believed to be lifelong.⁵ Also in contrast to HaT, SM can present with liver, spleen, and lymph node involvement; bone sclerosis; and cytopenia.^11,14

Mastocytosis is much rarer than HaT, with an estimated prevalence of 9 cases per 100,000 individuals in the United States.¹¹ Although HaT diagnostic testing is noninvasive, SM requires a bone marrow biopsy for definitive diagnosis. Given the likely much higher prevalence of HaT than SM and the patient burden of a bone marrow biopsy, HaT should be considered before proceeding with a bone marrow biopsy to evaluate for SM when a patient presents with persistent systemic symptoms of mast cell activation and elevated baseline tryptase levels. Furthermore, it also would be prudent to test for HaT in patients with known SM, as a cohort study by Lyons et al⁵ indicated that HaT is likely more common in those with SM (12.2% [10/82] of cohort with known SM vs 5.3% of 398 controls), and patients with concurrent SM and HaT were at a higher risk for severe anaphylaxis (RR=9.5; P=.007).

Studies thus far surrounding HaT have not evaluated timing of initial symptom onset or age of initial presentation for HaT. Furthermore, there is no guarantee that those with increased TPSAB1 copy number will be symptomatic, as there have been reports of asymptomatic individuals with HaT who had basal serum levels greater than 8 ng/mL.⁷ As research into HaT continues and larger cohorts are evaluated, questions surrounding timing of symptom onset and various factors that may make someone more likely to display a particular phenotype will be answered.

Treatment—Long-term prognosis for individuals with HaT is largely unknown. Unfortunately, there are limited data to support a single effective treatment strategy for managing HaT, and treatment has varied based on predominant symptoms. For cutaneous and GI tract symptoms, trials of maximal H₁ and H₂ antihistamines twice daily have been recommended.⁴ Omalizumab was reported to improve chronic urticaria in 3 of 3 patients, showing potential promise as a treatment.⁴ Mast cell stabilizers, such as oral cromolyn, have been used for severe GI symptoms, while some patients also have reported improvement with oral ketotifen.⁶ Other medications, such as tricyclic antidepressants, clemastine fumarate, and gabapentin, have been beneficial anecdotally.⁶ Given the lack of harmful effects seen in individuals who are α-tryptase deficient, α-tryptase inhibition is an intriguing target for future therapies.

Conclusion

Patients who present with a constellation of dermatologic, allergic, GI tract, neuropsychiatric, respiratory, autonomic, and connective tissue abnormalities consistent with HaT may receive a prompt diagnosis if the association is recognized. The full relationship between HaT and other chronic dermatologic disorders is still unknown. Ultimately, heightened interest and research into HaT will lead to more treatment options available for affected patients.

Hereditary alpha tryptasemia (HaT), an autosomal-dominant disorder of tryptase overproduction, was first described in 2014 by Lyons et al.¹ It has been associated with multiple dermatologic, allergic, gastrointestinal (GI) tract, neuropsychiatric, respiratory, autonomic, and connective tissue abnormalities. These multisystem concerns may include cutaneous flushing, chronic pruritus, urticaria, GI tract symptoms, arthralgia, and autonomic dysfunction.² The diverse symptoms and the recent discovery of HaT make recognition of this disorder challenging. Currently, it also is believed that HaT is associated with an elevated risk for anaphylaxis and is a biomarker for severe symptoms in disorders with increased mast cell burden such as mastocytosis.^3-5

Given the potential cutaneous manifestations and the fact that dermatologic symptoms may be the initial presentation of HaT, awareness and recognition of this condition by dermatologists are essential for diagnosis and treatment. This review summarizes the cutaneous presentations consistent with HaT and discusses various conditions that share overlapping dermatologic symptoms with HaT.

Background on HaT

Mast cells are known to secrete several vasoactive mediators including tryptase and histamine when activated by foreign substances, similar to IgE-mediated hypersensitivity reactions. In their baseline state, mast cells continuously secrete immature forms of tryptases called protryptases.⁶ These protryptases come in 2 forms: α and β. Although mature tryptase is acutely elevatedin anaphylaxis, persistently elevated total serum tryptase levels frequently are regarded as indicative of a systemic mast cell disorder such as systemic mastocytosis (SM).³ Despite the wide-ranging phenotype of HaT, all individuals with the disorder have an elevated basal serum tryptase level (>8 ng/mL). Hereditary alpha tryptasemia has been identified as another possible cause of persistently elevated levels.^2,6

Genetics and Epidemiology of HaT—The humantryptase locus at chromosome 16p13.3 is composed of 4 paralog genes: TPSG1, TPSB2, TPSAB1, and TPSD1.⁴ Only TPSAB1 encodes for α-tryptase, while both TPSB2 and TPSAB1 encode for β-tryptase.⁴ Hereditary alpha tryptasemia is an autosomal-dominant disorder resulting from a copy number increase in the α-tryptase encoding sequence within the TPSAB1 gene. Despite the wide-ranging phenotype of HaT, all individuals identified with the disorder have a basal serum tryptase level greater than 8 ng/mL, with mean (SD) levels of 15 (5) ng/mL and 24 (6) ng/mL with gene duplication and triplication, respectively (reference range, 0–11.4 ng/mL).^2,6 Hereditary alpha tryptasemia likely is common and largely undiagnosed, with a recently estimated prevalence of 5% in the United Kingdom⁷ and 5.6% in a cohort of 125 individuals from Italy, Slovenia, and the United States.⁵

Implications of Increased α-tryptase Levels—After an inciting stimulus, the active portions of α-protryptase and β-protryptase are secreted as tetramers by activated mast cells via degranulation. In vitro, β-tryptase homotetramers have been found to play a role in anaphylaxis, while α-homotetramers are nearly inactive.^8,9 Recently, however, it has been discovered that α2β2 tetramers also can form and do so in a higher ratio in individuals with increased α-tryptase–encoding gene copies, such as those with HaT.⁸ These heterotetramers exhibit unique properties compared with the homotetramers and may stimulate epidermal growth factor–like module-containing mucinlike hormone receptor 2 and protease-activated receptor 2 (PAR2). Epidermal growth factor–like module-containing mucinlike hormone receptor 2 activation likely contributes to vibratory urticaria in patients, while activation of PAR2 may have a range of clinical effects, including worsening asthma, inflammatory bowel disease, pruritus, and the exacerbation of dermal inflammation and hyperalgesia.^8,10 Thus, α- and β-tryptase tetramers can be considered mediators that may influence the severity of disorders in which mast cells are naturally prevalent and likely contribute to the phenotype of those with HaT.⁷ Furthermore, these characteristics have been shown to potentially increase in severity with increasing tryptase levels and with increased TPSAB1 duplications.^1,2 In contrast, more than 25% of the population is deficient in α-tryptase without known deleterious effects.⁵

Cutaneous Manifestations of HaT

A case series reported by Lyons et al¹ in 2014 detailed persistent elevated basal serum tryptase levels in 9 families with an autosomal-dominant pattern of inheritance. In this cohort, 31 of 33 (94%) affected individuals had a history of atopic dermatitis (AD), and 26 of 33 (79%) affected individuals reported symptoms consistent with mast cell degranulation, including urticaria; flushing; and/or crampy abdominal pain unprovoked or triggered by heat, exercise, vibration, stress, certain foods, or minor physical stimulation.¹ A later report by Lyons et al² in 2016 identified the TPSAB1 α-tryptase–encoding sequence copy number increase as the causative entity for HaT by examining a group of 96 patients from 35 families with frequent recurrent cutaneous flushing and pruritus, sometimes associated with urticaria and sleep disruption. Flushing and pruritus were found in 45% (33/73) of those with a TPSAB1 duplication and 80% (12/15) of those with a triplication (P=.022), suggesting a gene dose effect regarding α-tryptase encoding sequence copy number and these symptoms.²

A 2019 study further explored the clinical finding of urticaria in patients with HaT by specifically examining if vibration-induced urticaria was affected by TPSAB1 gene dosage.⁸ A cohort of 56 volunteers—35 healthy and 21 with HaT—underwent tryptase genotyping and cutaneous vibratory challenge. The presence of TPSAB1 was significantly correlated with induction of vibration-induced urticaria (P<.01), as the severity and prevalence of the urticarial response increased along with α- and β-tryptase gene ratios.⁸

Urticaria and angioedema also were seen in 51% (36/70) of patients in a cohort of HaT patients in the United Kingdom, in which 41% (29/70) also had skin flushing. In contrast to prior studies, these manifestations were not more common in patients with gene triplications or quintuplications than those with duplications.⁷ In another recent retrospective evaluation conducted at Brigham and Women’s Hospital (Boston, Massachusetts)(N=101), 80% of patients aged 4 to 85 years with confirmed diagnoses of HaT had skin manifestations such as urticaria, flushing, and pruritus.⁴

HaT and Mast Cell Activation Syndrome—In 2019, a Mast Cell Disorders Committee Work Group Report outlined recommendations for diagnosing and treating primary mast cell activation syndrome (MCAS), a disorder in which mast cells seem to be more easily activated. Mast cell activation syndrome is defined as a primary clinical condition in which there are episodic signs and symptoms of systemic anaphylaxis (Table) concurrently affecting at least 2 organ systems, resulting from secreted mast cell mediators.^9,11 The 2019 report also touched on clinical criteria that lack precision for diagnosing MCAS yet are in use, including dermographism and several types of rashes.⁹ Episode triggers frequent in MCAS include hot water, alcohol, stress, exercise, infection, hormonal changes, and physical stimuli.

Hereditary alpha tryptasemia has been suggested to be a risk factor for MCAS, which also can be associated with SM and clonal MCAS.⁹ Patients with MCAS should be tested for increased α-tryptase gene copy number given the overlap in symptoms, the likely predisposition of those with HaT to develop MCAS, and the fact that these patients could be at an increased risk for anaphylaxis.^4,7,9,11 However, the clinical phenotype for HaT includes allergic disorders affecting the skin as well as neuropsychiatric and connective tissue abnormalities that are distinctive from MCAS. Although HaT may be considered a heritable risk factor for MCAS, MCAS is only 1 potential phenotype associated with HaT.⁹

Implications of HaT

Hereditary alpha tryptasemia should be considered in all patients with basal tryptase levels greater than 8 ng/mL. Cutaneous symptoms are among the most common presentations for individuals with HaT and can include AD, chronic or episodic urticaria, pruritus, flushing, and angioedema. However, HaT is unique because of the coupling of these common dermatologic findings with other abnormalities, including abdominal pain and diarrhea, hypermobile joints, and autonomic dysfunction. Patients with HaT also may manifest psychiatric concerns of anxiety, depression, and chronic pain, all of which have been linked to this disorder.

It is unclear in HaT if the presence of extra-allelic copies of tryptase in an individual is directly pathogenic. The effects of increased basal tryptase and α2β2 tetramers have been shown to likely be responsible for some of the clinical features in these individuals but also may magnify other individual underlying disease(s) or diathesis in which mast cells are naturally abundant.⁸ In the skin, this increased mast cell activation and subsequent histamine release frequently are visible as dermatographia and urticaria. However, mast cell numbers also are known to be increased in both psoriatic and AD skin lesions,¹² thus severe presentation of these diseases in conjunction with the other symptoms associated with mast cell activation should prompt suspicion for HaT.

Effects of HaT on Other Cutaneous Disease—Given the increase of mast cells in AD skin lesions and fact that 94% of patients in the 2014 Lyons et al¹ study cited a history of AD, HaT may be a risk factor in the development of AD. Interestingly, in addition to the increased mast cells in AD lesions, PAR2+ nerve fibers also are increased in AD lesions and have been implicated in the nonhistaminergic pruritus experienced by patients with AD.¹² Thus, given the proposed propensity for α2β2 tetramers to activate PAR2, it is possible this mechanism may contribute to severe pruritus in individuals with AD and concurrent HaT, as those with HaT express increased α2β2 tetramers. However, no study to date has directly compared AD symptoms in patients with concurrent HaT vs patients without it. Further research is needed on how HaT impacts other allergic and inflammatory skin diseases such as AD and psoriasis, but one may reasonably consider HaT when treating chronic inflammatory skin diseases refractory to typical interventions and/or severe presentations. Although HaT is an autosomal-dominant disorder, it is not detected by standard whole exome sequencing or microarrays. A commercial test is available, utilizing a buccal swab to test for TPSAB1 copy number.

HaT and Mast Cell Disorders—When evaluating someone with suspected HaT, it is important to screen for other symptoms of mast cell activation. For instance, in the GI tract increased mast cell activation results in activation of motor neurons and nociceptors and increases secretion and peristalsis with consequent bloating, abdominal pain, and diarrhea.¹⁰ Likewise, tryptase also has neuromodulatory effects that amplify the perception of pain and are likely responsible for the feelings of hyperalgesia reported in patients with HaT.¹³

There is substantial overlap in the clinical pictures of HaT and MCAS, and HaT is considered a heritable risk factor for MCAS. Consequently, any patient undergoing workup for MCAS also should be tested for HaT. Although HaT is associated with consistently elevated tryptase, MCAS is episodic in nature, and an increase in tryptase levels of at least 20% plus 2 ng/mL from baseline only in the presence of other symptoms reflective of mast cell activation (Table) is a prerequisite for diagnosis.⁹ Chronic signs and symptoms of atopy, chronic urticaria, and severe asthma are not indicative of MCAS but are frequently seen in HaT.

Another cause of persistently elevated tryptase levels is SM. Systemic mastocytosis is defined by aberrant clonal mast cell expansion and systemic involvement¹¹ and can cause persistent symptoms, unlike MCAS alone. However, SM also can be associated with MCAS.⁹ Notably, a baseline serum tryptase level greater than 20 ng/mL—much higher than the threshold of greater than 8 ng/mL for suspicion of HaT—is seen in 75% of SM cases and is part of the minor diagnostic criteria for the disease.^9,11 However, the 2016 study identifying increased TPSAB1 α-tryptase–encoding sequences as the causative entity for HaT by Lyons et al² found the average (SD) basal serum tryptase level in individuals with α-tryptase–encoding sequence duplications to be 15 (5) ng/mL and 24 (6) ng/mL in those with triplications. Thus, there likely is no threshold for elevated baseline tryptase levels that would indicate SM over HaT as a more likely diagnosis. However, SM will present with new persistently elevated tryptase levels, whereas the elevation in HaT is believed to be lifelong.⁵ Also in contrast to HaT, SM can present with liver, spleen, and lymph node involvement; bone sclerosis; and cytopenia.^11,14

Mastocytosis is much rarer than HaT, with an estimated prevalence of 9 cases per 100,000 individuals in the United States.¹¹ Although HaT diagnostic testing is noninvasive, SM requires a bone marrow biopsy for definitive diagnosis. Given the likely much higher prevalence of HaT than SM and the patient burden of a bone marrow biopsy, HaT should be considered before proceeding with a bone marrow biopsy to evaluate for SM when a patient presents with persistent systemic symptoms of mast cell activation and elevated baseline tryptase levels. Furthermore, it also would be prudent to test for HaT in patients with known SM, as a cohort study by Lyons et al⁵ indicated that HaT is likely more common in those with SM (12.2% [10/82] of cohort with known SM vs 5.3% of 398 controls), and patients with concurrent SM and HaT were at a higher risk for severe anaphylaxis (RR=9.5; P=.007).

Studies thus far surrounding HaT have not evaluated timing of initial symptom onset or age of initial presentation for HaT. Furthermore, there is no guarantee that those with increased TPSAB1 copy number will be symptomatic, as there have been reports of asymptomatic individuals with HaT who had basal serum levels greater than 8 ng/mL.⁷ As research into HaT continues and larger cohorts are evaluated, questions surrounding timing of symptom onset and various factors that may make someone more likely to display a particular phenotype will be answered.

Treatment—Long-term prognosis for individuals with HaT is largely unknown. Unfortunately, there are limited data to support a single effective treatment strategy for managing HaT, and treatment has varied based on predominant symptoms. For cutaneous and GI tract symptoms, trials of maximal H₁ and H₂ antihistamines twice daily have been recommended.⁴ Omalizumab was reported to improve chronic urticaria in 3 of 3 patients, showing potential promise as a treatment.⁴ Mast cell stabilizers, such as oral cromolyn, have been used for severe GI symptoms, while some patients also have reported improvement with oral ketotifen.⁶ Other medications, such as tricyclic antidepressants, clemastine fumarate, and gabapentin, have been beneficial anecdotally.⁶ Given the lack of harmful effects seen in individuals who are α-tryptase deficient, α-tryptase inhibition is an intriguing target for future therapies.

Conclusion

Patients who present with a constellation of dermatologic, allergic, GI tract, neuropsychiatric, respiratory, autonomic, and connective tissue abnormalities consistent with HaT may receive a prompt diagnosis if the association is recognized. The full relationship between HaT and other chronic dermatologic disorders is still unknown. Ultimately, heightened interest and research into HaT will lead to more treatment options available for affected patients.

Hereditary alpha tryptasemia (HaT), an autosomal-dominant disorder of tryptase overproduction, was first described in 2014 by Lyons et al.¹ It has been associated with multiple dermatologic, allergic, gastrointestinal (GI) tract, neuropsychiatric, respiratory, autonomic, and connective tissue abnormalities. These multisystem concerns may include cutaneous flushing, chronic pruritus, urticaria, GI tract symptoms, arthralgia, and autonomic dysfunction.² The diverse symptoms and the recent discovery of HaT make recognition of this disorder challenging. Currently, it also is believed that HaT is associated with an elevated risk for anaphylaxis and is a biomarker for severe symptoms in disorders with increased mast cell burden such as mastocytosis.^3-5

Given the potential cutaneous manifestations and the fact that dermatologic symptoms may be the initial presentation of HaT, awareness and recognition of this condition by dermatologists are essential for diagnosis and treatment. This review summarizes the cutaneous presentations consistent with HaT and discusses various conditions that share overlapping dermatologic symptoms with HaT.

Background on HaT

Mast cells are known to secrete several vasoactive mediators including tryptase and histamine when activated by foreign substances, similar to IgE-mediated hypersensitivity reactions. In their baseline state, mast cells continuously secrete immature forms of tryptases called protryptases.⁶ These protryptases come in 2 forms: α and β. Although mature tryptase is acutely elevatedin anaphylaxis, persistently elevated total serum tryptase levels frequently are regarded as indicative of a systemic mast cell disorder such as systemic mastocytosis (SM).³ Despite the wide-ranging phenotype of HaT, all individuals with the disorder have an elevated basal serum tryptase level (>8 ng/mL). Hereditary alpha tryptasemia has been identified as another possible cause of persistently elevated levels.^2,6

Genetics and Epidemiology of HaT—The humantryptase locus at chromosome 16p13.3 is composed of 4 paralog genes: TPSG1, TPSB2, TPSAB1, and TPSD1.⁴ Only TPSAB1 encodes for α-tryptase, while both TPSB2 and TPSAB1 encode for β-tryptase.⁴ Hereditary alpha tryptasemia is an autosomal-dominant disorder resulting from a copy number increase in the α-tryptase encoding sequence within the TPSAB1 gene. Despite the wide-ranging phenotype of HaT, all individuals identified with the disorder have a basal serum tryptase level greater than 8 ng/mL, with mean (SD) levels of 15 (5) ng/mL and 24 (6) ng/mL with gene duplication and triplication, respectively (reference range, 0–11.4 ng/mL).^2,6 Hereditary alpha tryptasemia likely is common and largely undiagnosed, with a recently estimated prevalence of 5% in the United Kingdom⁷ and 5.6% in a cohort of 125 individuals from Italy, Slovenia, and the United States.⁵

Implications of Increased α-tryptase Levels—After an inciting stimulus, the active portions of α-protryptase and β-protryptase are secreted as tetramers by activated mast cells via degranulation. In vitro, β-tryptase homotetramers have been found to play a role in anaphylaxis, while α-homotetramers are nearly inactive.^8,9 Recently, however, it has been discovered that α2β2 tetramers also can form and do so in a higher ratio in individuals with increased α-tryptase–encoding gene copies, such as those with HaT.⁸ These heterotetramers exhibit unique properties compared with the homotetramers and may stimulate epidermal growth factor–like module-containing mucinlike hormone receptor 2 and protease-activated receptor 2 (PAR2). Epidermal growth factor–like module-containing mucinlike hormone receptor 2 activation likely contributes to vibratory urticaria in patients, while activation of PAR2 may have a range of clinical effects, including worsening asthma, inflammatory bowel disease, pruritus, and the exacerbation of dermal inflammation and hyperalgesia.^8,10 Thus, α- and β-tryptase tetramers can be considered mediators that may influence the severity of disorders in which mast cells are naturally prevalent and likely contribute to the phenotype of those with HaT.⁷ Furthermore, these characteristics have been shown to potentially increase in severity with increasing tryptase levels and with increased TPSAB1 duplications.^1,2 In contrast, more than 25% of the population is deficient in α-tryptase without known deleterious effects.⁵

Cutaneous Manifestations of HaT

A case series reported by Lyons et al¹ in 2014 detailed persistent elevated basal serum tryptase levels in 9 families with an autosomal-dominant pattern of inheritance. In this cohort, 31 of 33 (94%) affected individuals had a history of atopic dermatitis (AD), and 26 of 33 (79%) affected individuals reported symptoms consistent with mast cell degranulation, including urticaria; flushing; and/or crampy abdominal pain unprovoked or triggered by heat, exercise, vibration, stress, certain foods, or minor physical stimulation.¹ A later report by Lyons et al² in 2016 identified the TPSAB1 α-tryptase–encoding sequence copy number increase as the causative entity for HaT by examining a group of 96 patients from 35 families with frequent recurrent cutaneous flushing and pruritus, sometimes associated with urticaria and sleep disruption. Flushing and pruritus were found in 45% (33/73) of those with a TPSAB1 duplication and 80% (12/15) of those with a triplication (P=.022), suggesting a gene dose effect regarding α-tryptase encoding sequence copy number and these symptoms.²

A 2019 study further explored the clinical finding of urticaria in patients with HaT by specifically examining if vibration-induced urticaria was affected by TPSAB1 gene dosage.⁸ A cohort of 56 volunteers—35 healthy and 21 with HaT—underwent tryptase genotyping and cutaneous vibratory challenge. The presence of TPSAB1 was significantly correlated with induction of vibration-induced urticaria (P<.01), as the severity and prevalence of the urticarial response increased along with α- and β-tryptase gene ratios.⁸

Urticaria and angioedema also were seen in 51% (36/70) of patients in a cohort of HaT patients in the United Kingdom, in which 41% (29/70) also had skin flushing. In contrast to prior studies, these manifestations were not more common in patients with gene triplications or quintuplications than those with duplications.⁷ In another recent retrospective evaluation conducted at Brigham and Women’s Hospital (Boston, Massachusetts)(N=101), 80% of patients aged 4 to 85 years with confirmed diagnoses of HaT had skin manifestations such as urticaria, flushing, and pruritus.⁴

HaT and Mast Cell Activation Syndrome—In 2019, a Mast Cell Disorders Committee Work Group Report outlined recommendations for diagnosing and treating primary mast cell activation syndrome (MCAS), a disorder in which mast cells seem to be more easily activated. Mast cell activation syndrome is defined as a primary clinical condition in which there are episodic signs and symptoms of systemic anaphylaxis (Table) concurrently affecting at least 2 organ systems, resulting from secreted mast cell mediators.^9,11 The 2019 report also touched on clinical criteria that lack precision for diagnosing MCAS yet are in use, including dermographism and several types of rashes.⁹ Episode triggers frequent in MCAS include hot water, alcohol, stress, exercise, infection, hormonal changes, and physical stimuli.

Hereditary alpha tryptasemia has been suggested to be a risk factor for MCAS, which also can be associated with SM and clonal MCAS.⁹ Patients with MCAS should be tested for increased α-tryptase gene copy number given the overlap in symptoms, the likely predisposition of those with HaT to develop MCAS, and the fact that these patients could be at an increased risk for anaphylaxis.^4,7,9,11 However, the clinical phenotype for HaT includes allergic disorders affecting the skin as well as neuropsychiatric and connective tissue abnormalities that are distinctive from MCAS. Although HaT may be considered a heritable risk factor for MCAS, MCAS is only 1 potential phenotype associated with HaT.⁹

Implications of HaT

Hereditary alpha tryptasemia should be considered in all patients with basal tryptase levels greater than 8 ng/mL. Cutaneous symptoms are among the most common presentations for individuals with HaT and can include AD, chronic or episodic urticaria, pruritus, flushing, and angioedema. However, HaT is unique because of the coupling of these common dermatologic findings with other abnormalities, including abdominal pain and diarrhea, hypermobile joints, and autonomic dysfunction. Patients with HaT also may manifest psychiatric concerns of anxiety, depression, and chronic pain, all of which have been linked to this disorder.

It is unclear in HaT if the presence of extra-allelic copies of tryptase in an individual is directly pathogenic. The effects of increased basal tryptase and α2β2 tetramers have been shown to likely be responsible for some of the clinical features in these individuals but also may magnify other individual underlying disease(s) or diathesis in which mast cells are naturally abundant.⁸ In the skin, this increased mast cell activation and subsequent histamine release frequently are visible as dermatographia and urticaria. However, mast cell numbers also are known to be increased in both psoriatic and AD skin lesions,¹² thus severe presentation of these diseases in conjunction with the other symptoms associated with mast cell activation should prompt suspicion for HaT.

Effects of HaT on Other Cutaneous Disease—Given the increase of mast cells in AD skin lesions and fact that 94% of patients in the 2014 Lyons et al¹ study cited a history of AD, HaT may be a risk factor in the development of AD. Interestingly, in addition to the increased mast cells in AD lesions, PAR2+ nerve fibers also are increased in AD lesions and have been implicated in the nonhistaminergic pruritus experienced by patients with AD.¹² Thus, given the proposed propensity for α2β2 tetramers to activate PAR2, it is possible this mechanism may contribute to severe pruritus in individuals with AD and concurrent HaT, as those with HaT express increased α2β2 tetramers. However, no study to date has directly compared AD symptoms in patients with concurrent HaT vs patients without it. Further research is needed on how HaT impacts other allergic and inflammatory skin diseases such as AD and psoriasis, but one may reasonably consider HaT when treating chronic inflammatory skin diseases refractory to typical interventions and/or severe presentations. Although HaT is an autosomal-dominant disorder, it is not detected by standard whole exome sequencing or microarrays. A commercial test is available, utilizing a buccal swab to test for TPSAB1 copy number.

HaT and Mast Cell Disorders—When evaluating someone with suspected HaT, it is important to screen for other symptoms of mast cell activation. For instance, in the GI tract increased mast cell activation results in activation of motor neurons and nociceptors and increases secretion and peristalsis with consequent bloating, abdominal pain, and diarrhea.¹⁰ Likewise, tryptase also has neuromodulatory effects that amplify the perception of pain and are likely responsible for the feelings of hyperalgesia reported in patients with HaT.¹³

There is substantial overlap in the clinical pictures of HaT and MCAS, and HaT is considered a heritable risk factor for MCAS. Consequently, any patient undergoing workup for MCAS also should be tested for HaT. Although HaT is associated with consistently elevated tryptase, MCAS is episodic in nature, and an increase in tryptase levels of at least 20% plus 2 ng/mL from baseline only in the presence of other symptoms reflective of mast cell activation (Table) is a prerequisite for diagnosis.⁹ Chronic signs and symptoms of atopy, chronic urticaria, and severe asthma are not indicative of MCAS but are frequently seen in HaT.

Another cause of persistently elevated tryptase levels is SM. Systemic mastocytosis is defined by aberrant clonal mast cell expansion and systemic involvement¹¹ and can cause persistent symptoms, unlike MCAS alone. However, SM also can be associated with MCAS.⁹ Notably, a baseline serum tryptase level greater than 20 ng/mL—much higher than the threshold of greater than 8 ng/mL for suspicion of HaT—is seen in 75% of SM cases and is part of the minor diagnostic criteria for the disease.^9,11 However, the 2016 study identifying increased TPSAB1 α-tryptase–encoding sequences as the causative entity for HaT by Lyons et al² found the average (SD) basal serum tryptase level in individuals with α-tryptase–encoding sequence duplications to be 15 (5) ng/mL and 24 (6) ng/mL in those with triplications. Thus, there likely is no threshold for elevated baseline tryptase levels that would indicate SM over HaT as a more likely diagnosis. However, SM will present with new persistently elevated tryptase levels, whereas the elevation in HaT is believed to be lifelong.⁵ Also in contrast to HaT, SM can present with liver, spleen, and lymph node involvement; bone sclerosis; and cytopenia.^11,14

Mastocytosis is much rarer than HaT, with an estimated prevalence of 9 cases per 100,000 individuals in the United States.¹¹ Although HaT diagnostic testing is noninvasive, SM requires a bone marrow biopsy for definitive diagnosis. Given the likely much higher prevalence of HaT than SM and the patient burden of a bone marrow biopsy, HaT should be considered before proceeding with a bone marrow biopsy to evaluate for SM when a patient presents with persistent systemic symptoms of mast cell activation and elevated baseline tryptase levels. Furthermore, it also would be prudent to test for HaT in patients with known SM, as a cohort study by Lyons et al⁵ indicated that HaT is likely more common in those with SM (12.2% [10/82] of cohort with known SM vs 5.3% of 398 controls), and patients with concurrent SM and HaT were at a higher risk for severe anaphylaxis (RR=9.5; P=.007).

Studies thus far surrounding HaT have not evaluated timing of initial symptom onset or age of initial presentation for HaT. Furthermore, there is no guarantee that those with increased TPSAB1 copy number will be symptomatic, as there have been reports of asymptomatic individuals with HaT who had basal serum levels greater than 8 ng/mL.⁷ As research into HaT continues and larger cohorts are evaluated, questions surrounding timing of symptom onset and various factors that may make someone more likely to display a particular phenotype will be answered.

Treatment—Long-term prognosis for individuals with HaT is largely unknown. Unfortunately, there are limited data to support a single effective treatment strategy for managing HaT, and treatment has varied based on predominant symptoms. For cutaneous and GI tract symptoms, trials of maximal H₁ and H₂ antihistamines twice daily have been recommended.⁴ Omalizumab was reported to improve chronic urticaria in 3 of 3 patients, showing potential promise as a treatment.⁴ Mast cell stabilizers, such as oral cromolyn, have been used for severe GI symptoms, while some patients also have reported improvement with oral ketotifen.⁶ Other medications, such as tricyclic antidepressants, clemastine fumarate, and gabapentin, have been beneficial anecdotally.⁶ Given the lack of harmful effects seen in individuals who are α-tryptase deficient, α-tryptase inhibition is an intriguing target for future therapies.

Conclusion

Patients who present with a constellation of dermatologic, allergic, GI tract, neuropsychiatric, respiratory, autonomic, and connective tissue abnormalities consistent with HaT may receive a prompt diagnosis if the association is recognized. The full relationship between HaT and other chronic dermatologic disorders is still unknown. Ultimately, heightened interest and research into HaT will lead to more treatment options available for affected patients.

The Diagnosis: Pigmented Fungiform Papillae of the Tongue

Our patient’s hyperpigmentation was confined to the fungiform papillae, leading to a diagnosis of pigmented fungiform papillae of the tongue (PFPT). A biopsy was not performed, and reassurance was provided regarding the benign nature of this finding, which did not require treatment.

Pigmented fungiform papillae of the tongue is a benign, nonprogressive, asymptomatic pigmentary condition that is most common among patients with skin of color and typically develops within the second or third decade of life.^1,2 The pathogenesis is unclear, but activation of subepithelial melanophages without evidence of inflammation has been implicated.² Although no standard treatment exists, cosmetic improvement with the use of the Q-switched ruby laser has been reported.^3,4 Clinically, PFPT presents as asymptomatic hyperpigmentation confined to the fungiform papillae along the anterior and lateral portions of the tongue.^1,2

Pigmented fungiform papillae of the tongue typically is an isolated finding but rarely can be associated with hyperpigmentation of the nails (as in our patient) or gingiva.² Three different clinical patterns of presentation have been described: (1) a single well-circumscribed collection of pigmented fungiform papillae, (2) few scattered pigmented fungiform papillae admixed with many nonpigmented fungiform papillae, or (3) pigmentation of all fungiform papillae on the dorsal aspect of the tongue.^2,5,6 Pigmented fungiform papillae of the tongue is a clinical diagnosis based on visual recognition. Dermoscopic examination revealing a cobblestonelike or rose petal–like pattern may be helpful in diagnosing PFPT.^2,5-7 Although not typically recommended in the evaluation of PFPT, a biopsy will reveal papillary structures with hyperpigmentation of basilar keratinocytes as well as melanophages in the lamina propria.8 The latter finding suggests a transient inflammatory process despite the hallmark absence of inflammation.⁵ Melanocytic neoplasia and exogenous granules of pigment typically are not seen.⁸

Other conditions that may present with dark-colored macules or papules on the tongue should be considered in the evaluation of a patient with these clinical findings. Black hairy tongue (BHT), or lingua villosa nigra, is a benign finding due to filiform papillae hypertrophy on the dorsum of the tongue.⁹ Food particle debris caught in BHT can lead to porphyrin production by chromogenic bacteria and fungi. These porphyrins result in discoloration ranging from brown-black to yellow and green occurring anteriorly to the circumvallate papillae while usually sparing the tip and lateral sides of the tongue. Dermoscopy can show thin discolored fibers with a hairy appearance. Although normal filiform papillae are less than 1-mm long, 3-mm long papillae are considered diagnostic of BHT.⁹ Treatment includes effective oral hygiene and desquamation measures, which can lead to complete resolution.10

Peutz-Jeghers syndrome is a rare genodermatosis that is characterized by focal hyperpigmentation and multiple gastrointestinal mucosal hamartomatous polyps. Peutz-Jeghers syndrome should be suspected in a patient with discrete, 1- to 5-mm, brown to black macules on the perioral or periocular skin, tongue, genitals, palms, soles, and buccal mucosa with a history of abdominal symptoms.^11,12

Addison disease, or primary adrenal insufficiency, may present with brown hyperpigmentation on chronically sun-exposed areas; regions of friction or pressure; surrounding scar tissue; and mucosal surfaces such as the tongue, inner surface of the lip, and buccal and gingival mucosa.¹³ Addison disease is differentiated from PFPT by a more generalized hyperpigmentation due to increased melanin production as well as the presence of systemic symptoms related to hypocortisolism. The pigmentation seen on the buccal mucosa in Addison disease is patchy and diffuse, and histology reveals basal melanin hyperpigmentation with superficial dermal melanophages.¹³

Hereditary hemorrhagic telangiectasia is an inherited disorder featuring telangiectasia and generally appears in the third decade of life.¹⁴ Telangiectases classically are 1 to 3 mm in diameter with or without slight elevation. Dermoscopic findings include small red clots, lacunae, and serpentine or linear vessels arranged in a radial conformation surrounding a homogenous pink center.¹⁵ These telangiectases typically occur on the skin or mucosa, particularly the face, lips, tongue, nail beds, and nasal mucosa; however, any organ can be affected with arteriovenous malformations. Recurrent epistaxis occurs in more than half of patients with hereditary hemorrhagic telangiectasia.¹⁴ Histopathology reveals dilated vessels and lacunae near the dermoepidermal junction displacing the epidermis and papillary dermis.¹⁵ It is distinguished from PFPT by the vascular nature of the lesions and by the presence of other characteristic symptoms such as recurrent epistaxis and visceral arteriovenous malformations.

The Diagnosis: Pigmented Fungiform Papillae of the Tongue

Our patient’s hyperpigmentation was confined to the fungiform papillae, leading to a diagnosis of pigmented fungiform papillae of the tongue (PFPT). A biopsy was not performed, and reassurance was provided regarding the benign nature of this finding, which did not require treatment.

Pigmented fungiform papillae of the tongue is a benign, nonprogressive, asymptomatic pigmentary condition that is most common among patients with skin of color and typically develops within the second or third decade of life.^1,2 The pathogenesis is unclear, but activation of subepithelial melanophages without evidence of inflammation has been implicated.² Although no standard treatment exists, cosmetic improvement with the use of the Q-switched ruby laser has been reported.^3,4 Clinically, PFPT presents as asymptomatic hyperpigmentation confined to the fungiform papillae along the anterior and lateral portions of the tongue.^1,2

Pigmented fungiform papillae of the tongue typically is an isolated finding but rarely can be associated with hyperpigmentation of the nails (as in our patient) or gingiva.² Three different clinical patterns of presentation have been described: (1) a single well-circumscribed collection of pigmented fungiform papillae, (2) few scattered pigmented fungiform papillae admixed with many nonpigmented fungiform papillae, or (3) pigmentation of all fungiform papillae on the dorsal aspect of the tongue.^2,5,6 Pigmented fungiform papillae of the tongue is a clinical diagnosis based on visual recognition. Dermoscopic examination revealing a cobblestonelike or rose petal–like pattern may be helpful in diagnosing PFPT.^2,5-7 Although not typically recommended in the evaluation of PFPT, a biopsy will reveal papillary structures with hyperpigmentation of basilar keratinocytes as well as melanophages in the lamina propria.8 The latter finding suggests a transient inflammatory process despite the hallmark absence of inflammation.⁵ Melanocytic neoplasia and exogenous granules of pigment typically are not seen.⁸

Other conditions that may present with dark-colored macules or papules on the tongue should be considered in the evaluation of a patient with these clinical findings. Black hairy tongue (BHT), or lingua villosa nigra, is a benign finding due to filiform papillae hypertrophy on the dorsum of the tongue.⁹ Food particle debris caught in BHT can lead to porphyrin production by chromogenic bacteria and fungi. These porphyrins result in discoloration ranging from brown-black to yellow and green occurring anteriorly to the circumvallate papillae while usually sparing the tip and lateral sides of the tongue. Dermoscopy can show thin discolored fibers with a hairy appearance. Although normal filiform papillae are less than 1-mm long, 3-mm long papillae are considered diagnostic of BHT.⁹ Treatment includes effective oral hygiene and desquamation measures, which can lead to complete resolution.10

Peutz-Jeghers syndrome is a rare genodermatosis that is characterized by focal hyperpigmentation and multiple gastrointestinal mucosal hamartomatous polyps. Peutz-Jeghers syndrome should be suspected in a patient with discrete, 1- to 5-mm, brown to black macules on the perioral or periocular skin, tongue, genitals, palms, soles, and buccal mucosa with a history of abdominal symptoms.^11,12

Addison disease, or primary adrenal insufficiency, may present with brown hyperpigmentation on chronically sun-exposed areas; regions of friction or pressure; surrounding scar tissue; and mucosal surfaces such as the tongue, inner surface of the lip, and buccal and gingival mucosa.¹³ Addison disease is differentiated from PFPT by a more generalized hyperpigmentation due to increased melanin production as well as the presence of systemic symptoms related to hypocortisolism. The pigmentation seen on the buccal mucosa in Addison disease is patchy and diffuse, and histology reveals basal melanin hyperpigmentation with superficial dermal melanophages.¹³

Hereditary hemorrhagic telangiectasia is an inherited disorder featuring telangiectasia and generally appears in the third decade of life.¹⁴ Telangiectases classically are 1 to 3 mm in diameter with or without slight elevation. Dermoscopic findings include small red clots, lacunae, and serpentine or linear vessels arranged in a radial conformation surrounding a homogenous pink center.¹⁵ These telangiectases typically occur on the skin or mucosa, particularly the face, lips, tongue, nail beds, and nasal mucosa; however, any organ can be affected with arteriovenous malformations. Recurrent epistaxis occurs in more than half of patients with hereditary hemorrhagic telangiectasia.¹⁴ Histopathology reveals dilated vessels and lacunae near the dermoepidermal junction displacing the epidermis and papillary dermis.¹⁵ It is distinguished from PFPT by the vascular nature of the lesions and by the presence of other characteristic symptoms such as recurrent epistaxis and visceral arteriovenous malformations.

The Diagnosis: Pigmented Fungiform Papillae of the Tongue

Our patient’s hyperpigmentation was confined to the fungiform papillae, leading to a diagnosis of pigmented fungiform papillae of the tongue (PFPT). A biopsy was not performed, and reassurance was provided regarding the benign nature of this finding, which did not require treatment.

Pigmented fungiform papillae of the tongue is a benign, nonprogressive, asymptomatic pigmentary condition that is most common among patients with skin of color and typically develops within the second or third decade of life.^1,2 The pathogenesis is unclear, but activation of subepithelial melanophages without evidence of inflammation has been implicated.² Although no standard treatment exists, cosmetic improvement with the use of the Q-switched ruby laser has been reported.^3,4 Clinically, PFPT presents as asymptomatic hyperpigmentation confined to the fungiform papillae along the anterior and lateral portions of the tongue.^1,2

Pigmented fungiform papillae of the tongue typically is an isolated finding but rarely can be associated with hyperpigmentation of the nails (as in our patient) or gingiva.² Three different clinical patterns of presentation have been described: (1) a single well-circumscribed collection of pigmented fungiform papillae, (2) few scattered pigmented fungiform papillae admixed with many nonpigmented fungiform papillae, or (3) pigmentation of all fungiform papillae on the dorsal aspect of the tongue.^2,5,6 Pigmented fungiform papillae of the tongue is a clinical diagnosis based on visual recognition. Dermoscopic examination revealing a cobblestonelike or rose petal–like pattern may be helpful in diagnosing PFPT.^2,5-7 Although not typically recommended in the evaluation of PFPT, a biopsy will reveal papillary structures with hyperpigmentation of basilar keratinocytes as well as melanophages in the lamina propria.8 The latter finding suggests a transient inflammatory process despite the hallmark absence of inflammation.⁵ Melanocytic neoplasia and exogenous granules of pigment typically are not seen.⁸

Other conditions that may present with dark-colored macules or papules on the tongue should be considered in the evaluation of a patient with these clinical findings. Black hairy tongue (BHT), or lingua villosa nigra, is a benign finding due to filiform papillae hypertrophy on the dorsum of the tongue.⁹ Food particle debris caught in BHT can lead to porphyrin production by chromogenic bacteria and fungi. These porphyrins result in discoloration ranging from brown-black to yellow and green occurring anteriorly to the circumvallate papillae while usually sparing the tip and lateral sides of the tongue. Dermoscopy can show thin discolored fibers with a hairy appearance. Although normal filiform papillae are less than 1-mm long, 3-mm long papillae are considered diagnostic of BHT.⁹ Treatment includes effective oral hygiene and desquamation measures, which can lead to complete resolution.10

Peutz-Jeghers syndrome is a rare genodermatosis that is characterized by focal hyperpigmentation and multiple gastrointestinal mucosal hamartomatous polyps. Peutz-Jeghers syndrome should be suspected in a patient with discrete, 1- to 5-mm, brown to black macules on the perioral or periocular skin, tongue, genitals, palms, soles, and buccal mucosa with a history of abdominal symptoms.^11,12

Addison disease, or primary adrenal insufficiency, may present with brown hyperpigmentation on chronically sun-exposed areas; regions of friction or pressure; surrounding scar tissue; and mucosal surfaces such as the tongue, inner surface of the lip, and buccal and gingival mucosa.¹³ Addison disease is differentiated from PFPT by a more generalized hyperpigmentation due to increased melanin production as well as the presence of systemic symptoms related to hypocortisolism. The pigmentation seen on the buccal mucosa in Addison disease is patchy and diffuse, and histology reveals basal melanin hyperpigmentation with superficial dermal melanophages.¹³

Hereditary hemorrhagic telangiectasia is an inherited disorder featuring telangiectasia and generally appears in the third decade of life.¹⁴ Telangiectases classically are 1 to 3 mm in diameter with or without slight elevation. Dermoscopic findings include small red clots, lacunae, and serpentine or linear vessels arranged in a radial conformation surrounding a homogenous pink center.¹⁵ These telangiectases typically occur on the skin or mucosa, particularly the face, lips, tongue, nail beds, and nasal mucosa; however, any organ can be affected with arteriovenous malformations. Recurrent epistaxis occurs in more than half of patients with hereditary hemorrhagic telangiectasia.¹⁴ Histopathology reveals dilated vessels and lacunae near the dermoepidermal junction displacing the epidermis and papillary dermis.¹⁵ It is distinguished from PFPT by the vascular nature of the lesions and by the presence of other characteristic symptoms such as recurrent epistaxis and visceral arteriovenous malformations.

“More than Jews have kept Shabbat, Shabbat has kept the Jews.” – Ahad Ha’am

You should all be well rested by now. After all, we’ve just come through the festive shutdown of the holiday season where all of your pumpkin/peppermint/marshmallow flavored coffees were sipped while walking around in your jimjams at 10 a.m. It was the time of year for you to take time off to get a proper rest and be energized to get back to work. Yet, I’m not feeling it from you.

So let’s talk about burnout – just kidding, that would only make it worse. “Burned-out’’ is a hackneyed and defective phrase to describe what many of us are feeling. We are not “destroyed, gutted by fire or by overheating.” No, we are, as one of our docs put it to me: “Just tired.” Ah, a much better Old English word! “Tired” captures it. It means to feel “in need of rest.” We are not ruined, we are just depleted. We don’t need discarding. We need some rest.

Ironically, this column, like most of mine, comes to you after my having written it on a Saturday and Sunday. I also just logged on to my EMR and checked results, renewed a few prescriptions, and answered a couple messages. If I didn’t, my Monday’s work would be crushingly heavy.

Maybe I need to be more efficient and finish my work during the week. Or maybe I need to realize that work has not let up since about 600 BCE and taking one day off each week to rest is an obligation to myself, my family and my community.

I wonder if I can choose Mondays.

Dr. Benabio is director of Healthcare Transformation and chief of dermatology at Kaiser Permanente San Diego. The opinions expressed in this column are his own and do not represent those of Kaiser Permanente. Dr. Benabio is @Dermdoc on Twitter. Write to him at [email protected].

“More than Jews have kept Shabbat, Shabbat has kept the Jews.” – Ahad Ha’am

You should all be well rested by now. After all, we’ve just come through the festive shutdown of the holiday season where all of your pumpkin/peppermint/marshmallow flavored coffees were sipped while walking around in your jimjams at 10 a.m. It was the time of year for you to take time off to get a proper rest and be energized to get back to work. Yet, I’m not feeling it from you.

So let’s talk about burnout – just kidding, that would only make it worse. “Burned-out’’ is a hackneyed and defective phrase to describe what many of us are feeling. We are not “destroyed, gutted by fire or by overheating.” No, we are, as one of our docs put it to me: “Just tired.” Ah, a much better Old English word! “Tired” captures it. It means to feel “in need of rest.” We are not ruined, we are just depleted. We don’t need discarding. We need some rest.

Ironically, this column, like most of mine, comes to you after my having written it on a Saturday and Sunday. I also just logged on to my EMR and checked results, renewed a few prescriptions, and answered a couple messages. If I didn’t, my Monday’s work would be crushingly heavy.

Maybe I need to be more efficient and finish my work during the week. Or maybe I need to realize that work has not let up since about 600 BCE and taking one day off each week to rest is an obligation to myself, my family and my community.

I wonder if I can choose Mondays.

Dr. Benabio is director of Healthcare Transformation and chief of dermatology at Kaiser Permanente San Diego. The opinions expressed in this column are his own and do not represent those of Kaiser Permanente. Dr. Benabio is @Dermdoc on Twitter. Write to him at [email protected].

“More than Jews have kept Shabbat, Shabbat has kept the Jews.” – Ahad Ha’am

You should all be well rested by now. After all, we’ve just come through the festive shutdown of the holiday season where all of your pumpkin/peppermint/marshmallow flavored coffees were sipped while walking around in your jimjams at 10 a.m. It was the time of year for you to take time off to get a proper rest and be energized to get back to work. Yet, I’m not feeling it from you.

So let’s talk about burnout – just kidding, that would only make it worse. “Burned-out’’ is a hackneyed and defective phrase to describe what many of us are feeling. We are not “destroyed, gutted by fire or by overheating.” No, we are, as one of our docs put it to me: “Just tired.” Ah, a much better Old English word! “Tired” captures it. It means to feel “in need of rest.” We are not ruined, we are just depleted. We don’t need discarding. We need some rest.

Ironically, this column, like most of mine, comes to you after my having written it on a Saturday and Sunday. I also just logged on to my EMR and checked results, renewed a few prescriptions, and answered a couple messages. If I didn’t, my Monday’s work would be crushingly heavy.

Maybe I need to be more efficient and finish my work during the week. Or maybe I need to realize that work has not let up since about 600 BCE and taking one day off each week to rest is an obligation to myself, my family and my community.

I wonder if I can choose Mondays.

Dr. Benabio is director of Healthcare Transformation and chief of dermatology at Kaiser Permanente San Diego. The opinions expressed in this column are his own and do not represent those of Kaiser Permanente. Dr. Benabio is @Dermdoc on Twitter. Write to him at [email protected].

Contact dermatitis is a common problem in the floral bulb industry and is considered an occupational disease. Daffodils (Narcissus species)(Figure) are thought to be the most common cause of irritant contact dermatitis among florists.¹

Clinical Importance

Picking daffodils can start as early as October, when the flowers are still closed. The picker’s hand slides down the stem to snap the stalk at the base. This potentially traumatic maneuver to the web of the fingers leads to abrasions, which are irritated by the sap and cause granulomatous sores and paronychia. An experienced picker can pick 20,000 flowers a day, leading to extensive contact with sap.²

Eczematous or granulomatous rash on the arms also is seen as the sap irritates the wrist and forearm. The pickers often hold the flowers until a bunch of 10 has been collected. The 10 flowers are held together by a rubber band and stacked along the arm, the chin, and the axilla, causing the rash to extend to those areas. Sap also can be transferred by the hand to other parts of the body, such as the face. In men, sap can be transferred to the genitalia as the men urinate in the field.

Narcissus also can cause poisoning if ingested by humans or animals. Researchers who analyzed calls made to the New Zealand Natural Poisons Centre between 2003 and 2010 determined that daffodil was the 11th most common call for plant-related poisoning.³

Although the severity of plant poisoning often is low due to the small amount of plant material usually consumed, more severe poisoning can occur when the plant is eaten for medicinal purposes or mistaken for an edible plant.³ Vomiting, respiratory symptoms, abdominal pain, diarrhea, trembling, and convulsions can occur when daffodils are ingested. Death has been reported due to ingestion of the bulbs.⁴

In February 2010, 10 children aged 10 and 11 years and their 22-year-old guide presented to an emergency department in Israel after ingesting Narcissus bulbs, which were mistakenly believed to be the bulbs of onions.⁴ Eight children and the guide vomited. One child and the guide reported abdominal pain. All were discharged in stable condition after 4 hours of observation.⁴

Clinical Manifestations

Daffodil rash or lily rash was first described in 1910.⁵ The typical rash presents as dryness, fissures, scaling, and erythema of the fingertips, hands, and forearms, often with subungual hyperkeratosis. Vesicles and pustules may be seen. The rash may extend to other areas of the body, including the face.⁶

Use of protective gloves and clothing to avoid contact with the plant is recommended.² Treatment includes stopping contact with the irritant, eye irrigation, and supportive measures (airway, breathing, and circulation). Activated charcoal can be helpful if used within 1 hour after ingestion but is contraindicated in vomiting patients.⁴

Identifying Features

The genus Narcissus is in the family Amaryllidaceae and contains ornamental plants, including daffodil (trumpet Narcissus, Narcissus pseudonarcissus), jonquil (Narcissus jonquilla), and poet’s narcissus (Narcissus poeticus). Most species are perennial; the plant emerges from a bulb in spring. Leaves originate from the base of the plant and range from 5-cm to 1.2-meters long, depending on the species. The flowers span a range of shapes and colors—from a trumpet (the daffodil) to a ringlike cup (poet’s Narcissus) and in yellow, white, and pink.⁷

Distribution and Plant Facts

Distribution—There are approximately 80 to 100 wild Narcissus species, which are found in southwestern Europe, North Africa, the Balkan Peninsula, Italy, and France. There are more than 27,000 Narcissus cultivars registered in the International Daffodil Register.⁸

Plant Facts—The daffodil is the national flower of Wales. It also is often used to depict hope and joy and is the symbol of cancer charities in many countries.⁹

The name Narcissus is believed to have originated from Greek mythology. A handsome youth, Narcissus, fell in love with his own reflection, for which the gods punished him by turning him into a flower.¹⁰

Another theory states that Narcissus is derived from the Greek word narkao (to benumb) due to its narcotic properties. When an open wound is subjected to an extract of the bulb, numbness of the entire nervous system is said to occur as well as paralysis of the heart. This narcotic effect led Socrates to refer to the Narcissus plant as the “chaplet of the infernal gods.”¹¹

Narcissus is an important flower in various ethnic rituals. The Greeks often planted daffodils near tombs. In Muslim culture, white is believed to be the symbol of good and purity; Narcissus was one of the most common white-flowered plants found in Muslim graveyards.¹²

Medicinal Qualities and Uses—Narcissus species have been used as medicinal plants for a variety of ailments. For example, Narcissus tazetta contains flavonoids, alkaloids, saponins, tannins, cardiac glycosides, oil, steroids, terpenoids, and anthraquinones that contribute to its antibacterial, antifungal, antiviral, antimalarial, anticancer, antioxidant, dermatologic, cardiovascular, immunomodulatory, and acetylcholinesterase inhibitory effects.¹³ In a study, chloroform extracts from N tazetta bulbs were found to be more active than doxorubicin against hepatocellular and colon cancer cell lines.¹⁴

More than 500 alkaloids have been isolated from the Narcissus genus.¹⁵ In 2001, the US Food and Drug Administration approved one of the alkaloids, galantamine, for the treatment of mild to moderate stages of Alzheimer disease.¹⁶ Galantamine selectively and reversibly inhibits acetylcholinesterase, the enzyme believed responsible for neurodegeneration seen in Alzheimer disease. Plants are the main source of galantamine, despite the ability of pharmaceutical companies to synthesize the compound. Galantamine hydrobromide is sold by prescription (Razadyne [Janssen Pharmaceuticals, Inc]); generic formulations approved by the US Food and Drug Administration have been produced by more than 15 pharmaceutical companies.^17,18

Irritant and Allergen

Sap found in the bulbs and hollow stems of Narcissus contains calcium oxalate crystals, or raphides. The minute, needle-shaped calcium oxalate crystals are believed to be a waste product of cellular metabolism.¹⁹ When the plant structure is compromised by pickers snapping the stalk, the sharp crystals penetrate the skin to cause an irritant contact dermatitis.

Relevant Research—A study used electron microscopy to characterize the structure of raphides from various plants,² though not from Narcissus species; the structure of each raphide was then compared to the degree of irritation it produced. The researchers concluded that more elongated crystals (those containing barbs) produce a greater degree of irritation. Narcissus species are known to cause varying degrees of skin irritation: For example, N tazetta rarely causes skin irritation, whereas N pseudonarcissi (daffodil) tends to cause remarkably more skin irritation.²

Allergic reactions to and strong toxicity from Narcissus species are not well understood. In a study, only 2 alkaloids—homolycorine and masonin—produced a weakly positive reaction in patch tests on sensitized guinea pigs, which correlates with the finding of a different study, in which only 2 of 12 patients whose findings were examined over 14 years had a positive patch test for Narcissus.^20,21

However, IgE-mediated allergies indicative of an allergic response to Narcissus have been reported. A study isolated an allergenic protein, narcin, from bulbs of N tazetta. Narcin is a 13-kDa protein with potent allergenic effects capable of inducing production of proinflammatory cytokines and increasing IgE levels in mononuclear cells in peripheral blood.²²

More research is required to find and understand the compounds responsible for causing an allergic reaction to Narcissus.

Contact dermatitis is a common problem in the floral bulb industry and is considered an occupational disease. Daffodils (Narcissus species)(Figure) are thought to be the most common cause of irritant contact dermatitis among florists.¹

Clinical Importance

Picking daffodils can start as early as October, when the flowers are still closed. The picker’s hand slides down the stem to snap the stalk at the base. This potentially traumatic maneuver to the web of the fingers leads to abrasions, which are irritated by the sap and cause granulomatous sores and paronychia. An experienced picker can pick 20,000 flowers a day, leading to extensive contact with sap.²

Eczematous or granulomatous rash on the arms also is seen as the sap irritates the wrist and forearm. The pickers often hold the flowers until a bunch of 10 has been collected. The 10 flowers are held together by a rubber band and stacked along the arm, the chin, and the axilla, causing the rash to extend to those areas. Sap also can be transferred by the hand to other parts of the body, such as the face. In men, sap can be transferred to the genitalia as the men urinate in the field.

Narcissus also can cause poisoning if ingested by humans or animals. Researchers who analyzed calls made to the New Zealand Natural Poisons Centre between 2003 and 2010 determined that daffodil was the 11th most common call for plant-related poisoning.³

Although the severity of plant poisoning often is low due to the small amount of plant material usually consumed, more severe poisoning can occur when the plant is eaten for medicinal purposes or mistaken for an edible plant.³ Vomiting, respiratory symptoms, abdominal pain, diarrhea, trembling, and convulsions can occur when daffodils are ingested. Death has been reported due to ingestion of the bulbs.⁴

In February 2010, 10 children aged 10 and 11 years and their 22-year-old guide presented to an emergency department in Israel after ingesting Narcissus bulbs, which were mistakenly believed to be the bulbs of onions.⁴ Eight children and the guide vomited. One child and the guide reported abdominal pain. All were discharged in stable condition after 4 hours of observation.⁴

Clinical Manifestations

Daffodil rash or lily rash was first described in 1910.⁵ The typical rash presents as dryness, fissures, scaling, and erythema of the fingertips, hands, and forearms, often with subungual hyperkeratosis. Vesicles and pustules may be seen. The rash may extend to other areas of the body, including the face.⁶

Use of protective gloves and clothing to avoid contact with the plant is recommended.² Treatment includes stopping contact with the irritant, eye irrigation, and supportive measures (airway, breathing, and circulation). Activated charcoal can be helpful if used within 1 hour after ingestion but is contraindicated in vomiting patients.⁴

Identifying Features

The genus Narcissus is in the family Amaryllidaceae and contains ornamental plants, including daffodil (trumpet Narcissus, Narcissus pseudonarcissus), jonquil (Narcissus jonquilla), and poet’s narcissus (Narcissus poeticus). Most species are perennial; the plant emerges from a bulb in spring. Leaves originate from the base of the plant and range from 5-cm to 1.2-meters long, depending on the species. The flowers span a range of shapes and colors—from a trumpet (the daffodil) to a ringlike cup (poet’s Narcissus) and in yellow, white, and pink.⁷

Distribution and Plant Facts

Distribution—There are approximately 80 to 100 wild Narcissus species, which are found in southwestern Europe, North Africa, the Balkan Peninsula, Italy, and France. There are more than 27,000 Narcissus cultivars registered in the International Daffodil Register.⁸

Plant Facts—The daffodil is the national flower of Wales. It also is often used to depict hope and joy and is the symbol of cancer charities in many countries.⁹

The name Narcissus is believed to have originated from Greek mythology. A handsome youth, Narcissus, fell in love with his own reflection, for which the gods punished him by turning him into a flower.¹⁰

Another theory states that Narcissus is derived from the Greek word narkao (to benumb) due to its narcotic properties. When an open wound is subjected to an extract of the bulb, numbness of the entire nervous system is said to occur as well as paralysis of the heart. This narcotic effect led Socrates to refer to the Narcissus plant as the “chaplet of the infernal gods.”¹¹

Narcissus is an important flower in various ethnic rituals. The Greeks often planted daffodils near tombs. In Muslim culture, white is believed to be the symbol of good and purity; Narcissus was one of the most common white-flowered plants found in Muslim graveyards.¹²

Medicinal Qualities and Uses—Narcissus species have been used as medicinal plants for a variety of ailments. For example, Narcissus tazetta contains flavonoids, alkaloids, saponins, tannins, cardiac glycosides, oil, steroids, terpenoids, and anthraquinones that contribute to its antibacterial, antifungal, antiviral, antimalarial, anticancer, antioxidant, dermatologic, cardiovascular, immunomodulatory, and acetylcholinesterase inhibitory effects.¹³ In a study, chloroform extracts from N tazetta bulbs were found to be more active than doxorubicin against hepatocellular and colon cancer cell lines.¹⁴

More than 500 alkaloids have been isolated from the Narcissus genus.¹⁵ In 2001, the US Food and Drug Administration approved one of the alkaloids, galantamine, for the treatment of mild to moderate stages of Alzheimer disease.¹⁶ Galantamine selectively and reversibly inhibits acetylcholinesterase, the enzyme believed responsible for neurodegeneration seen in Alzheimer disease. Plants are the main source of galantamine, despite the ability of pharmaceutical companies to synthesize the compound. Galantamine hydrobromide is sold by prescription (Razadyne [Janssen Pharmaceuticals, Inc]); generic formulations approved by the US Food and Drug Administration have been produced by more than 15 pharmaceutical companies.^17,18

Irritant and Allergen

Sap found in the bulbs and hollow stems of Narcissus contains calcium oxalate crystals, or raphides. The minute, needle-shaped calcium oxalate crystals are believed to be a waste product of cellular metabolism.¹⁹ When the plant structure is compromised by pickers snapping the stalk, the sharp crystals penetrate the skin to cause an irritant contact dermatitis.

Relevant Research—A study used electron microscopy to characterize the structure of raphides from various plants,² though not from Narcissus species; the structure of each raphide was then compared to the degree of irritation it produced. The researchers concluded that more elongated crystals (those containing barbs) produce a greater degree of irritation. Narcissus species are known to cause varying degrees of skin irritation: For example, N tazetta rarely causes skin irritation, whereas N pseudonarcissi (daffodil) tends to cause remarkably more skin irritation.²

Allergic reactions to and strong toxicity from Narcissus species are not well understood. In a study, only 2 alkaloids—homolycorine and masonin—produced a weakly positive reaction in patch tests on sensitized guinea pigs, which correlates with the finding of a different study, in which only 2 of 12 patients whose findings were examined over 14 years had a positive patch test for Narcissus.^20,21

However, IgE-mediated allergies indicative of an allergic response to Narcissus have been reported. A study isolated an allergenic protein, narcin, from bulbs of N tazetta. Narcin is a 13-kDa protein with potent allergenic effects capable of inducing production of proinflammatory cytokines and increasing IgE levels in mononuclear cells in peripheral blood.²²

More research is required to find and understand the compounds responsible for causing an allergic reaction to Narcissus.

Contact dermatitis is a common problem in the floral bulb industry and is considered an occupational disease. Daffodils (Narcissus species)(Figure) are thought to be the most common cause of irritant contact dermatitis among florists.¹

Clinical Importance

Picking daffodils can start as early as October, when the flowers are still closed. The picker’s hand slides down the stem to snap the stalk at the base. This potentially traumatic maneuver to the web of the fingers leads to abrasions, which are irritated by the sap and cause granulomatous sores and paronychia. An experienced picker can pick 20,000 flowers a day, leading to extensive contact with sap.²

Eczematous or granulomatous rash on the arms also is seen as the sap irritates the wrist and forearm. The pickers often hold the flowers until a bunch of 10 has been collected. The 10 flowers are held together by a rubber band and stacked along the arm, the chin, and the axilla, causing the rash to extend to those areas. Sap also can be transferred by the hand to other parts of the body, such as the face. In men, sap can be transferred to the genitalia as the men urinate in the field.

Narcissus also can cause poisoning if ingested by humans or animals. Researchers who analyzed calls made to the New Zealand Natural Poisons Centre between 2003 and 2010 determined that daffodil was the 11th most common call for plant-related poisoning.³

Although the severity of plant poisoning often is low due to the small amount of plant material usually consumed, more severe poisoning can occur when the plant is eaten for medicinal purposes or mistaken for an edible plant.³ Vomiting, respiratory symptoms, abdominal pain, diarrhea, trembling, and convulsions can occur when daffodils are ingested. Death has been reported due to ingestion of the bulbs.⁴

In February 2010, 10 children aged 10 and 11 years and their 22-year-old guide presented to an emergency department in Israel after ingesting Narcissus bulbs, which were mistakenly believed to be the bulbs of onions.⁴ Eight children and the guide vomited. One child and the guide reported abdominal pain. All were discharged in stable condition after 4 hours of observation.⁴

Clinical Manifestations

Daffodil rash or lily rash was first described in 1910.⁵ The typical rash presents as dryness, fissures, scaling, and erythema of the fingertips, hands, and forearms, often with subungual hyperkeratosis. Vesicles and pustules may be seen. The rash may extend to other areas of the body, including the face.⁶

Use of protective gloves and clothing to avoid contact with the plant is recommended.² Treatment includes stopping contact with the irritant, eye irrigation, and supportive measures (airway, breathing, and circulation). Activated charcoal can be helpful if used within 1 hour after ingestion but is contraindicated in vomiting patients.⁴

Identifying Features

The genus Narcissus is in the family Amaryllidaceae and contains ornamental plants, including daffodil (trumpet Narcissus, Narcissus pseudonarcissus), jonquil (Narcissus jonquilla), and poet’s narcissus (Narcissus poeticus). Most species are perennial; the plant emerges from a bulb in spring. Leaves originate from the base of the plant and range from 5-cm to 1.2-meters long, depending on the species. The flowers span a range of shapes and colors—from a trumpet (the daffodil) to a ringlike cup (poet’s Narcissus) and in yellow, white, and pink.⁷

Distribution and Plant Facts

Distribution—There are approximately 80 to 100 wild Narcissus species, which are found in southwestern Europe, North Africa, the Balkan Peninsula, Italy, and France. There are more than 27,000 Narcissus cultivars registered in the International Daffodil Register.⁸

Plant Facts—The daffodil is the national flower of Wales. It also is often used to depict hope and joy and is the symbol of cancer charities in many countries.⁹

The name Narcissus is believed to have originated from Greek mythology. A handsome youth, Narcissus, fell in love with his own reflection, for which the gods punished him by turning him into a flower.¹⁰

Another theory states that Narcissus is derived from the Greek word narkao (to benumb) due to its narcotic properties. When an open wound is subjected to an extract of the bulb, numbness of the entire nervous system is said to occur as well as paralysis of the heart. This narcotic effect led Socrates to refer to the Narcissus plant as the “chaplet of the infernal gods.”¹¹

Narcissus is an important flower in various ethnic rituals. The Greeks often planted daffodils near tombs. In Muslim culture, white is believed to be the symbol of good and purity; Narcissus was one of the most common white-flowered plants found in Muslim graveyards.¹²

Medicinal Qualities and Uses—Narcissus species have been used as medicinal plants for a variety of ailments. For example, Narcissus tazetta contains flavonoids, alkaloids, saponins, tannins, cardiac glycosides, oil, steroids, terpenoids, and anthraquinones that contribute to its antibacterial, antifungal, antiviral, antimalarial, anticancer, antioxidant, dermatologic, cardiovascular, immunomodulatory, and acetylcholinesterase inhibitory effects.¹³ In a study, chloroform extracts from N tazetta bulbs were found to be more active than doxorubicin against hepatocellular and colon cancer cell lines.¹⁴

More than 500 alkaloids have been isolated from the Narcissus genus.¹⁵ In 2001, the US Food and Drug Administration approved one of the alkaloids, galantamine, for the treatment of mild to moderate stages of Alzheimer disease.¹⁶ Galantamine selectively and reversibly inhibits acetylcholinesterase, the enzyme believed responsible for neurodegeneration seen in Alzheimer disease. Plants are the main source of galantamine, despite the ability of pharmaceutical companies to synthesize the compound. Galantamine hydrobromide is sold by prescription (Razadyne [Janssen Pharmaceuticals, Inc]); generic formulations approved by the US Food and Drug Administration have been produced by more than 15 pharmaceutical companies.^17,18

Irritant and Allergen

Sap found in the bulbs and hollow stems of Narcissus contains calcium oxalate crystals, or raphides. The minute, needle-shaped calcium oxalate crystals are believed to be a waste product of cellular metabolism.¹⁹ When the plant structure is compromised by pickers snapping the stalk, the sharp crystals penetrate the skin to cause an irritant contact dermatitis.

Relevant Research—A study used electron microscopy to characterize the structure of raphides from various plants,² though not from Narcissus species; the structure of each raphide was then compared to the degree of irritation it produced. The researchers concluded that more elongated crystals (those containing barbs) produce a greater degree of irritation. Narcissus species are known to cause varying degrees of skin irritation: For example, N tazetta rarely causes skin irritation, whereas N pseudonarcissi (daffodil) tends to cause remarkably more skin irritation.²

Allergic reactions to and strong toxicity from Narcissus species are not well understood. In a study, only 2 alkaloids—homolycorine and masonin—produced a weakly positive reaction in patch tests on sensitized guinea pigs, which correlates with the finding of a different study, in which only 2 of 12 patients whose findings were examined over 14 years had a positive patch test for Narcissus.^20,21

However, IgE-mediated allergies indicative of an allergic response to Narcissus have been reported. A study isolated an allergenic protein, narcin, from bulbs of N tazetta. Narcin is a 13-kDa protein with potent allergenic effects capable of inducing production of proinflammatory cytokines and increasing IgE levels in mononuclear cells in peripheral blood.²²

More research is required to find and understand the compounds responsible for causing an allergic reaction to Narcissus.

Nonmelanoma skin cancer (NMSC) is the most common cancer in the United States, and cutaneous melanoma is projected to be the fifth most common form of cancer in 2022, with increasing incidence and high potential for mortality.^1-3 Estimates indicate that 35% to 45% of all cancers in White patients are cutaneous, with 4% to 5% occurring in Hispanic patients, 2% to 4% in Asian patients, and 1% to 2% in Black patients.⁴ Of the keratinocyte carcinomas, basal cell carcinoma (BCC) is the most prevalent, projected to affect approximately 33% to 39% of White males and 23% to 28% of White females in the United States during their lifetimes. Squamous cell carcinoma (SCC) is the second most common skin malignancy, with a lifetime risk of 9% to 14% for White males and 4% to 9% for White females in the United States.⁵ The incidence of melanoma continues to increase, with approximately 99,780 new cases expected in the United States in 2022.¹

UV-induced DNA damage plays a key role in the pathogenesis and development of various skin malignancies.⁶ UV radiation from sunlight or tanning devices causes photocarcinogenesis due to molecular and cellular effects, including the generation of reactive oxygen species, DNA damage due to the formation of cyclobutane pyrimidine dimers and pyrimidine-pyrimidone, melanogenesis, apoptosis, and the increased expression of harmful genes and proteins.⁶ The summation of this damage can result in skin malignancies, including NMSC and melanoma.^6,7 Dietary antioxidants theoretically help prevent oxidative reactions from occurring within the body, and it has been suggested that intake of dietary antioxidants may decrease DNA damage and prevent tumorigenesis secondary to UV radiation.⁸ Antioxidants exist naturally in the body but can be acquired exogenously. Investigators have studied dietary antioxidants in preventing skin cancer formation with promising results in the laboratory setting.^8-11 Recently, more robust human studies have been initiated to further delineate this relationship. We present clinical evidence of several frequently utilized antioxidant vitamins and their effects on melanoma and NMSC.

Antioxidants

Vitamin A—Vitamin A is a fat-soluble vitamin found in animal sources, including fish, liver, and eggs. Carotenoids, such as beta carotene, are provitamin A plant derivatives found in fruits and vegetables that are converted into biologically active retinol and retinoic acid.¹² Retinols play a key role in cellular growth and differentiation and are thought to be protective against skin cancer via the inactivation of free radicals and immunologic enhancement due to their antiproliferative, antioxidative, and antiapoptotic effects.^13-16 Animal studies have demonstrated this protective effect and the ability of retinoids to suppress carcinogenesis; however, human studies reveal conflicting results.^17,18

Greenberg et al¹⁹ investigated the use of beta carotene in preventing the formation of NMSC. Patients (N=1805) were randomized to receive 50 mg of beta carotene daily or placebo. Over a 5-year period, there was no significant reduction in the occurrence of NMSC (relative risk [RR], 1.05; 95% CI, 0.91-1.22).¹⁹ Frieling et al²⁰ conducted a similar randomized, double-blind, placebo-controlled trial investigating beta carotene for primary prevention of NMSC in 22,071 healthy male physicians. The study group received 50 mg of beta carotene every other day for 12 years’ duration, and there was no significant effect on the incidence of first NMSC development (RR, 0.98; 95% CI, 0.92-1.05).²⁰

A case-control study by Naldi et al²¹ found an inverse association between vitamin A intake and development of melanoma. Study participants were stratified into quartiles based on level of dietary intake and found an odds ratio (OR) of 0.71 for beta carotene (95% CI, 0.50-1.02), 0.57 for retinol (95% CI, 0.39-0.83), and 0.51 for total vitamin A (95% CI, 0.35-0.75) when comparing the upper quartile of vitamin A intake to the lower quartile. Upper-quartile cutoff values of vitamin A intake were 214 µg/d for beta carotene, 149 µg/d for retinol, and 359 µg/d for total vitamin A.²¹ More recently, a meta-analysis by Zhang et al²² pooled data from 8 case-control studies and 2 prospective studies. Intake of retinol but not total vitamin A or beta carotene was associated with a reduced risk for development of melanoma (retinol: OR, 0.80; 95% CI, 0.69-0.92; total vitamin A: OR, 0.86; 95% CI, 0.59-1.25; beta carotene: OR, 0.87; 95% CI, 0.62-1.20).²² Feskanich et al²³ demonstrated similar findings with use of food-frequency questionnaires in White women, suggesting that retinol intake from food combined with supplements may be protective for women who were otherwise at a low risk for melanoma based on nondietary factors. These factors included painful or blistering sunburns during childhood, history of more than 6 sunburns, more than 3 moles on the left arm, having red or blonde hair, and having a parent or sibling with melanoma (P=.01). However, this relationship did not hold true when looking at women at an intermediate or high risk for melanoma (P=.16 and P=.46).²³

When looking at high-risk patients, such as transplant patients, oral retinoids have been beneficial in preventing NMSC.^24-27 Bavinck et al²⁴ investigated 44 renal transplant patients with a history of more than 10 NMSCs treated with 30 mg of acitretin daily vs placebo. Patients receiving oral retinoid supplementation developed fewer NMSCs over a 6-month treatment period (P=.01).²⁴ Similarly, George et al²⁵ investigated acitretin in renal transplant patients and found a statistically significant decrease in number of SCCs in patients on supplementation (P=.002). Solomon-Cohen et al²⁶ performed a retrospective case-crossover study in solid organ transplant recipients and found that those treated with 10 mg of acitretin daily for 2 years had a significant reduction in the number of new keratinocyte carcinomas (P=.002). Other investigators have demonstrated similar results, and in 2006, Otley et al²⁷ proposed standardized dosing of acitretin for chemoprevention in high-risk patients, including patients developing 5 to 10 NMSCs per year, solid organ transplant recipients, and those with syndromes associated with the development of NMSC.^28,29 Overall, in the general population, vitamin A and related compounds have not demonstrated a significant association with decreased development of NMSC; however, oral retinoids have proven useful for high-risk patients. Furthermore, several studies have suggested a negative association between vitamin A levels and the incidence of melanoma, specifically in the retinol formulation. 

Vitamin B₃—Nicotinamide (also known as niacinamide) is a water-soluble form of vitamin B₃ and is obtained from animal-based and plant-based foods, such as meat, fish, and legumes.³⁰ Nicotinamide plays a key role in cellular metabolism, cellular signaling, and DNA repair, including protection from UV damage within keratinocytes.^31,32 Early mouse models demonstrated decreased formation of skin tumors in mice treated with topical or oral nicotinamide.^32,33 A number of human studies have revealed similar results.^34-36

Chen et al³⁴ conducted the ONTRAC study, a phase 3, double-blind, randomized controlled trial (RCT) looking at 386 participants with a history of at least 2 NMSCs in the preceding 5 years. At 12 months, those treated with 500 mg of nicotinamide twice daily demonstrated a statistically significant decreased rate of SCC formation (P=.05). A decreased incidence of BCC development was noted; however, this trend did not reach statistical significance (P=.12). Precancerous skin lesions also were found to be decreased in the treatment group, with 20% lower incidence of actinic keratoses (AKs) after 9 months of treatment (P<.001).³⁴ Drago et al³⁵ specifically studied the incidence of AKs in 38 transplant recipients—8 liver and 30 kidney—and found that previously noted AKs had decreased in size for 18 of 19 patients taking 500 mg of nicotinamide daily when originally photographed AKs were remeasured at 6-month follow-up, with 7 of these 18 patients demonstrating complete clinical regression. Of those on nicotinamide supplementation, no new AKs developed compared to the control group, which demonstrated increased size of AKs or development of new AKs in 91% of patients, with 7 AKs progressing into SCC.³⁵

Nicotinamide has been demonstrated to be useful in preventing skin cancer in high-risk populations, such as transplant patients or those with a high incidence of NMSC.^34,36 Despite promising results within the laboratory setting, nicotinamide’s effects on melanoma in humans remains less clear.^31,37 Studies suggest that nicotinamide enhances tumor-infiltrating lymphocytes and DNA repair mechanisms in melanocytes, which may translate into nicotinamide, providing chemoprevention for melanoma, but research in human patients is limited.^31,37

Vitamin B₉—Folate, the natural form of vitamin B₉, is a water-soluble compound that is found in many foods, especially green leafy vegetables, and often is supplemented because of its health benefits.^38,39 In the skin, folic acid plays a key role in cellular replication and proliferation.³⁸ Controversy exists regarding folate’s effects on cellular growth and turnover with respect to cancer incidence.^38,40 Donnenfeld et al⁴¹ conducted a prospective study assessing dietary folic acid intake and development of NMSC. A total of 5880 participants completed dietary records throughout the first 2 years of the study. After an average follow-up period of 12.6 years, there was an overall increased incidence of skin cancer in those with increased dietary folate (P=.03). Furthermore, when striating by skin cancer type, there was an increased incidence of NMSC overall as well as BCC when analyzing by type of NMSC (P=.03 for NMSC; P=.05 for BCC). However, when stratifying by gender, these findings only held true for women.⁴¹ Similar effects were observed by Fung et al,⁴² who prospectively studied the intake of various vitamins in relationship to the development of BCC in women. During 12 years of follow-up, a positive association was observed between folate intake and BCC development (OR, 1.2; 95% CI, 1.10-1.31).⁴² Fung et al⁴³ also investigated the role of several vitamins in the development of SCC and found that folate showed a negative association, which did not reach statistical significance (RR, 0.79; 95% CI, 0.56-1.11). Furthermore, Vollset et al⁴⁰ conducted a meta-analysis comparing folic acid to placebo in the incidence of various types of cancer. The study excluded NMSC but reported no significant association between the development of melanoma and folic acid supplementation.⁴⁰ In summary, the effects of folate have diverse consequences, potentially promoting the formation of NMSC, but studies suggest that an individual’s gender and other genetic and environmental factors also may play a role.

Vitamin C—Vitamin C (also known as ascorbic acid) is a water-soluble vitamin with antioxidant immune-mediating effects. It is found in various fruits and vegetables and serves as a cofactor for enzymes within the body playing a key role in immune function and collagen formation.^44,45 It has been postulated that ascorbic acid can provide protection from UV radiation damage via its intracellular activity but conversely can contribute to oxidative damage.⁴⁴ Multiple in vitro laboratory studies and animal models have demonstrated photoprotective effects of ascorbic acid.^46-48 Despite these findings, minimal photoprotective effects have been found in the human population.

Kune et al⁴⁹ performed a case-control study of 88 males with previously diagnosed NMSC undergoing surgical removal and investigated patients’ prior dietary habits. Patients with NMSC had a statistically significantly lower level of vitamin C–containing food in their diet than those without NMSC (P=.004).⁴⁹ In addition, Vural et al⁵⁰ analyzed plasma samples and blood cells of patients with AK and BCC and found a significant decrease in ascorbic acid levels in both the AK (P<.001) and BCC (P<.001) groups compared with controls. However, studies have found that consumption of certain dietary compounds can rapidly increase plasma concentration levels, which may serve as a major confounding variable in this study. Plasma concentrations of ascorbic acid and beta carotene were found to be significantly increased following consumption of a high-antioxidant diet for as short a duration as 2 weeks (P<.05).⁵¹ More recently, Heinen et al⁵² performed a prospective study on 1001 adults. In patients without a history of skin cancer, they found that vitamin C from food sources plus dietary supplements was positively associated with the development of BCC (P=.03).⁵² Similarly, Fung et al⁴² performed a study in women and found a positive association between vitamin C intake and the development of BCC (OR, 1.13; 95% CI, 1.03-1.23).

The relationship between vitamin C intake—either in dietary or supplemental form—and melanoma remains controversial. Mice-based studies found that high concentrations of orally administered vitamin C induce cytotoxicity in melanoma cell lines, but at low concentrations they promote tumor growth of malignant melanoma.⁵³ Feskanich et al²³ examined the relationship between vitamin C intake and melanoma development via food frequency questionnaires in White women and found that vitamin C was associated with a higher risk for melanoma (P=.05), and furthermore, a positive dose response with frequency of orange juice intake was observed (P=.008). Overall, despite promising laboratory studies, there is a lack of RCTs investigating the use of vitamin C supplementation for prevention of NMSC and melanoma in humans, and the oral benefits of vitamin C for chemoprevention remain unclear.

Vitamin D—Vitamin D is a fat-soluble vitamin that is found in fish, liver, egg, and cheese, and is endogenously produced when UV radiation from sun exposure interacts with the skin, triggering the synthesis of vitamin D.⁵⁴ Vitamin D is biologically inactive and must be converted to its active form 1,25-dihydroxyvitamin D after entering the body. Vitamin D modulates many genes involved in cellular proliferation and differentiation.⁵⁴ Vitamin D receptors are expressed on keratinocytes and melanocytes.⁵⁵ Animal studies have demonstrated a potentially protective effect of vitamin D in the development of NMSC.⁵⁶ In a mouse model, Ellison et al⁵⁶ found that mice without vitamin D receptors developed skin tumors more rapidly than those with vitamin D receptors.

Unfortunately, these findings have not been demonstrated in humans, and studies have even reported an increased risk for development of NMSC in patients with normal or increased vitamin D levels compared with those with low levels of vitamin D.^57-60 Eide et al⁵⁷ studied 3223 patients seeking advice for low bone density by recording their vitamin D levels at the time of presentation and monitoring development of NMSC. Vitamin D levels greater than 15 ng/mL were positively associated with the development of NMSC (OR, 1.7; 95% CI, 1.04-2.7). This association held true for both SCC and BCC, with a higher risk estimated for SCC (OR, 3.2; 95% CI, 0.4-24.0 for SCC; OR, 1.7; 95% CI, 0.5-5.8 for BCC).⁵⁷ An increased vitamin D serum level also was found to be significantly associated with a higher risk for BCC and melanoma by van der Pols et al.⁵⁸ This prospective study looked at the incidence of skin cancer over 11 years. Study participants with vitamin D levels over 75 nmol/L more frequently developed BCC (P=.01) and melanoma (P=.05). In contrast, SCC was less frequently observed in participants with these high levels of vitamin D (P=.07).⁵⁸ Furthermore, Park et al⁶⁰ looked at vitamin D and skin cancer risk for men and women in the United States and found no association with risk for SCC or melanoma but a positive association with BCC (P=.05 for total vitamin D; P<.01 for dietary vitamin D). Additional studies have been performed with inconsistent results, and multiple authors suggest the possible confounding relationship between vitamin D levels and UV radiation exposure.^59-62 Furthermore, some studies have even demonstrated a negative association between vitamin D and NMSC. Tang et al⁶³ performed a retrospective case-control study in elderly males, investigating serum levels of vitamin D and patients’ self-reported history of NMSC, which demonstrated that higher levels of vitamin D were associated with a decreased risk for NMSC. Overall, the relationship between vitamin D and skin cancer development remains unclear for both melanoma and NMSC.

Vitamin E—Vitamin E is a fat-soluble vitamin that is found in plant-based oils, nuts, seeds, fruits, and vegetables.⁶⁴ It works as an antioxidant to protect against free radicals and heighten immune function, and it also serves as a pro-oxidant.^65,66 Vitamin E naturally exists in 8 chemical forms, of which gamma-tocopherol is the most frequently obtained form in the diet, and alpha-tocopherol is the most abundant form found in the body.^64,65

Early animal studies demonstrated the inhibition of UV-induced damage in mice receiving vitamin E supplementation.^67,68 Human studies have not consistently shown these effects. Vural et al⁵⁰ investigated plasma samples and blood cells of patients with AKs and BCCs and reported a significant decrease in alpha-tocopherol levels in both the AK (P<.05) and BCC (P<.001) groups compared with controls. However, studies also have demonstrated a positive association between vitamin E intake and the development of BCC, including one by Fung et al,⁴² which found a significant association in women (OR, 1.15; 95% CI, 1.06-1.26).

Vitamin E has been found to inhibit melanin synthesis in the laboratory, suggesting a potentially protective effect in melanoma.^69,70 However, in the study performed by Feskanich et al²³ examining vitamin intake and melanoma incidence via food-frequency questionnaires, vitamin E was not associated with a lower risk for melanoma. Despite promising laboratory studies, the data surrounding the use of a vitamin E supplement for prevention of melanoma and NMSC in humans remains unclear.

Selenium—Selenium is a trace mineral found in plants, meat, and fish. It plays a key role in reproduction, hormone metabolism, DNA synthesis, and protection from oxidative damage.⁷¹ In mice studies, lack of selenium-containing proteins resulted in skin abnormalities, including the development of a hyperplastic epidermis and aberrant hair follicle morphogenesis with alopecia after birth, and numerous experimental studies have demonstrated a negative association between selenium intake and cancer.^72,73 However, human studies have yielded alternative results. 

The Nutritional Prevention of Cancer Study Group analyzed 1312 dermatology patients with a history of NMSC.⁷⁴ The study population was obtained from 7 dermatology clinics with randomization to control for confounding variables. Study participants received either 200 μg of selenium daily or placebo.⁷⁴ Baseline characteristics of each study group were overall balanced. Selenium intake was found to have no effect on the development of BCC (hazard ratio [HR], 1.09; 95% CI, 0.94-1.26) but an increased risk for developing SCC (HR, 1.25; 95% CI, 1.03-1.51) and total NMSC (HR, 1.17; 95% CI, 1.02-1.34).^74,75 Similarly, Reid et al⁷⁶ performed an RCT comparing patients treated with 400 μg/d of selenium to those treated with 200 μg/d of selenium. When compared with placebo, those treated with 200 μg/d of selenium had a statistically significantly increased incidence of NMSC (P=.006); however, those treated with 400 μg/d of selenium had no significant change in total incidence of NMSC (P=.51).⁷⁶ Furthermore, Vinceti et al⁷⁷ performed a review of 83 studies from the literature investigating the effect of dietary selenium, and from the RCTs, there was no beneficial effect of selenium in reducing cancer risk in general; however, some studies demonstrated an increased incidence of other types of cancer, including melanoma. Of the RCTs included in the study investigating NMSC incidence specifically, it was found that the incidence was not affected by selenium administration (RR, 1.16; 95% CI, 0.30-4.42; 2 studies, 2027 participants).⁷⁷ Despite data from several studies demonstrating an increased risk for NMSC, the effects of selenium on the risk for NMSC and melanoma remain unclear. 

Combination Antioxidant Studies

In addition to investigating the use of single antioxidants in skin cancer prevention, studies utilizing the combination of various antioxidants or other dietary minerals have been conducted. Hercberg et al⁷⁸ performed a randomized, double-blinded, placebo-controlled trial of 13,017 adults (7876 women and 5141 men) receiving a combination of 120 mg vitamin C, 30 mg vitamin E, 100 μg selenium, 6 mg beta carotene, and 20 mg zinc. Study participants were followed for an average of 7.5 years, and the development of skin cancers were recorded. Overall, the incidence rate of skin cancer did not differ between the 2 treatment groups; however, when segregated by gender, the study found that there was an increased risk for developing skin cancer in women taking the antioxidant supplement combination compared with placebo (P=.03). This difference was not observed in the 2 treatment groups of male patients (P=.11). When looking specifically at NMSC, there was no difference between treatment groups for male or female patients (P=.39 for males; P=.15 for females). In contrast, there was a higher incidence of melanoma identified in female patients taking the combination antioxidant supplement (P=.01), but this was not seen within the male study population (P=.51).⁷⁸ In addition, Chang et al⁷⁹ performed a meta-analysis of 10 previously published RCTs. Analysis revealed that treatment with a variety of supplements, including vitamins A, C, E, and beta carotene, were found to have no preventative effects on the incidence of skin cancer development (RR, 0.98; CI, 0.98-1.03). Notable limitations to this study included the variability in protocols of the studies included in this meta-analysis, the limited number of RCTs investigating vitamin supplementation and the risk for skin cancer development, and the influence of dietary intake on study outcomes.⁷⁹

Other Dietary Agents

Furocoumarins—Furocoumarins are botanical substances found in various fruits and plants, including many citrus products. Furocoumarins are activated by UV light radiation and can lead to development of a phototoxic eruption. Several studies have suggested a pharmacogenetic effect of furocoumarins.⁸⁰ Sun et al⁸⁰ collected dietary data from 47,453 men and 75,291 women on furocoumarin intake and correlation with the development of NMSC. Overall, the study suggested that the intake of furocoumarins may lead to an increase in the development of BCC (HR, 1.16; 95% CI, 1.11-1.21; P=.002); however, there was no significant association identified between total intake of furocoumarins in the risk for SCC or melanoma.⁸⁰ Furthermore, Sakaki et al⁸¹ conducted a survey study looking at the consumption of citrus products and the development of NMSC. The group found that there was an increased risk for NMSC in those consuming an increased amount of citrus products (P=.007).⁸¹

Conclusion

Dietary antioxidants have been investigated for their potential role in the prevention of tumorigenesis. Specific antioxidant vitamins, such as vitamin A derivatives and niacinamide, have demonstrated clinical utility in the prevention of NMSC in high-risk populations. Retinol also has been associated with a reduced incidence of melanoma. Numerous antioxidants have demonstrated promising data within the laboratory setting; however, inconsistent results have been appreciated in humans. Furthermore, several research studies suggest that folate, vitamin D, and furocoumarins may be associated with an increased risk for skin cancer development; however, these studies are inconclusive, and dietary studies are challenging to conduct. Overall, RCTs investigating the role of antioxidants for chemoprevention are limited. Moreover, the study of dietary antioxidants and vitamins may be affected by various confounding variables that can be difficult to account for because of patients’ potentially poor recall of dietary intake and the effect of dietary intake in supplemental studies. Given the increasing prevalence of skin cancer worldwide, further research into the clinical utility of antioxidants in skin cancer prevention is warranted. 

Nonmelanoma skin cancer (NMSC) is the most common cancer in the United States, and cutaneous melanoma is projected to be the fifth most common form of cancer in 2022, with increasing incidence and high potential for mortality.^1-3 Estimates indicate that 35% to 45% of all cancers in White patients are cutaneous, with 4% to 5% occurring in Hispanic patients, 2% to 4% in Asian patients, and 1% to 2% in Black patients.⁴ Of the keratinocyte carcinomas, basal cell carcinoma (BCC) is the most prevalent, projected to affect approximately 33% to 39% of White males and 23% to 28% of White females in the United States during their lifetimes. Squamous cell carcinoma (SCC) is the second most common skin malignancy, with a lifetime risk of 9% to 14% for White males and 4% to 9% for White females in the United States.⁵ The incidence of melanoma continues to increase, with approximately 99,780 new cases expected in the United States in 2022.¹

UV-induced DNA damage plays a key role in the pathogenesis and development of various skin malignancies.⁶ UV radiation from sunlight or tanning devices causes photocarcinogenesis due to molecular and cellular effects, including the generation of reactive oxygen species, DNA damage due to the formation of cyclobutane pyrimidine dimers and pyrimidine-pyrimidone, melanogenesis, apoptosis, and the increased expression of harmful genes and proteins.⁶ The summation of this damage can result in skin malignancies, including NMSC and melanoma.^6,7 Dietary antioxidants theoretically help prevent oxidative reactions from occurring within the body, and it has been suggested that intake of dietary antioxidants may decrease DNA damage and prevent tumorigenesis secondary to UV radiation.⁸ Antioxidants exist naturally in the body but can be acquired exogenously. Investigators have studied dietary antioxidants in preventing skin cancer formation with promising results in the laboratory setting.^8-11 Recently, more robust human studies have been initiated to further delineate this relationship. We present clinical evidence of several frequently utilized antioxidant vitamins and their effects on melanoma and NMSC.

Antioxidants

Vitamin A—Vitamin A is a fat-soluble vitamin found in animal sources, including fish, liver, and eggs. Carotenoids, such as beta carotene, are provitamin A plant derivatives found in fruits and vegetables that are converted into biologically active retinol and retinoic acid.¹² Retinols play a key role in cellular growth and differentiation and are thought to be protective against skin cancer via the inactivation of free radicals and immunologic enhancement due to their antiproliferative, antioxidative, and antiapoptotic effects.^13-16 Animal studies have demonstrated this protective effect and the ability of retinoids to suppress carcinogenesis; however, human studies reveal conflicting results.^17,18

Greenberg et al¹⁹ investigated the use of beta carotene in preventing the formation of NMSC. Patients (N=1805) were randomized to receive 50 mg of beta carotene daily or placebo. Over a 5-year period, there was no significant reduction in the occurrence of NMSC (relative risk [RR], 1.05; 95% CI, 0.91-1.22).¹⁹ Frieling et al²⁰ conducted a similar randomized, double-blind, placebo-controlled trial investigating beta carotene for primary prevention of NMSC in 22,071 healthy male physicians. The study group received 50 mg of beta carotene every other day for 12 years’ duration, and there was no significant effect on the incidence of first NMSC development (RR, 0.98; 95% CI, 0.92-1.05).²⁰

A case-control study by Naldi et al²¹ found an inverse association between vitamin A intake and development of melanoma. Study participants were stratified into quartiles based on level of dietary intake and found an odds ratio (OR) of 0.71 for beta carotene (95% CI, 0.50-1.02), 0.57 for retinol (95% CI, 0.39-0.83), and 0.51 for total vitamin A (95% CI, 0.35-0.75) when comparing the upper quartile of vitamin A intake to the lower quartile. Upper-quartile cutoff values of vitamin A intake were 214 µg/d for beta carotene, 149 µg/d for retinol, and 359 µg/d for total vitamin A.²¹ More recently, a meta-analysis by Zhang et al²² pooled data from 8 case-control studies and 2 prospective studies. Intake of retinol but not total vitamin A or beta carotene was associated with a reduced risk for development of melanoma (retinol: OR, 0.80; 95% CI, 0.69-0.92; total vitamin A: OR, 0.86; 95% CI, 0.59-1.25; beta carotene: OR, 0.87; 95% CI, 0.62-1.20).²² Feskanich et al²³ demonstrated similar findings with use of food-frequency questionnaires in White women, suggesting that retinol intake from food combined with supplements may be protective for women who were otherwise at a low risk for melanoma based on nondietary factors. These factors included painful or blistering sunburns during childhood, history of more than 6 sunburns, more than 3 moles on the left arm, having red or blonde hair, and having a parent or sibling with melanoma (P=.01). However, this relationship did not hold true when looking at women at an intermediate or high risk for melanoma (P=.16 and P=.46).²³

When looking at high-risk patients, such as transplant patients, oral retinoids have been beneficial in preventing NMSC.^24-27 Bavinck et al²⁴ investigated 44 renal transplant patients with a history of more than 10 NMSCs treated with 30 mg of acitretin daily vs placebo. Patients receiving oral retinoid supplementation developed fewer NMSCs over a 6-month treatment period (P=.01).²⁴ Similarly, George et al²⁵ investigated acitretin in renal transplant patients and found a statistically significant decrease in number of SCCs in patients on supplementation (P=.002). Solomon-Cohen et al²⁶ performed a retrospective case-crossover study in solid organ transplant recipients and found that those treated with 10 mg of acitretin daily for 2 years had a significant reduction in the number of new keratinocyte carcinomas (P=.002). Other investigators have demonstrated similar results, and in 2006, Otley et al²⁷ proposed standardized dosing of acitretin for chemoprevention in high-risk patients, including patients developing 5 to 10 NMSCs per year, solid organ transplant recipients, and those with syndromes associated with the development of NMSC.^28,29 Overall, in the general population, vitamin A and related compounds have not demonstrated a significant association with decreased development of NMSC; however, oral retinoids have proven useful for high-risk patients. Furthermore, several studies have suggested a negative association between vitamin A levels and the incidence of melanoma, specifically in the retinol formulation. 

Vitamin B₃—Nicotinamide (also known as niacinamide) is a water-soluble form of vitamin B₃ and is obtained from animal-based and plant-based foods, such as meat, fish, and legumes.³⁰ Nicotinamide plays a key role in cellular metabolism, cellular signaling, and DNA repair, including protection from UV damage within keratinocytes.^31,32 Early mouse models demonstrated decreased formation of skin tumors in mice treated with topical or oral nicotinamide.^32,33 A number of human studies have revealed similar results.^34-36

Chen et al³⁴ conducted the ONTRAC study, a phase 3, double-blind, randomized controlled trial (RCT) looking at 386 participants with a history of at least 2 NMSCs in the preceding 5 years. At 12 months, those treated with 500 mg of nicotinamide twice daily demonstrated a statistically significant decreased rate of SCC formation (P=.05). A decreased incidence of BCC development was noted; however, this trend did not reach statistical significance (P=.12). Precancerous skin lesions also were found to be decreased in the treatment group, with 20% lower incidence of actinic keratoses (AKs) after 9 months of treatment (P<.001).³⁴ Drago et al³⁵ specifically studied the incidence of AKs in 38 transplant recipients—8 liver and 30 kidney—and found that previously noted AKs had decreased in size for 18 of 19 patients taking 500 mg of nicotinamide daily when originally photographed AKs were remeasured at 6-month follow-up, with 7 of these 18 patients demonstrating complete clinical regression. Of those on nicotinamide supplementation, no new AKs developed compared to the control group, which demonstrated increased size of AKs or development of new AKs in 91% of patients, with 7 AKs progressing into SCC.³⁵

Nicotinamide has been demonstrated to be useful in preventing skin cancer in high-risk populations, such as transplant patients or those with a high incidence of NMSC.^34,36 Despite promising results within the laboratory setting, nicotinamide’s effects on melanoma in humans remains less clear.^31,37 Studies suggest that nicotinamide enhances tumor-infiltrating lymphocytes and DNA repair mechanisms in melanocytes, which may translate into nicotinamide, providing chemoprevention for melanoma, but research in human patients is limited.^31,37

Vitamin B₉—Folate, the natural form of vitamin B₉, is a water-soluble compound that is found in many foods, especially green leafy vegetables, and often is supplemented because of its health benefits.^38,39 In the skin, folic acid plays a key role in cellular replication and proliferation.³⁸ Controversy exists regarding folate’s effects on cellular growth and turnover with respect to cancer incidence.^38,40 Donnenfeld et al⁴¹ conducted a prospective study assessing dietary folic acid intake and development of NMSC. A total of 5880 participants completed dietary records throughout the first 2 years of the study. After an average follow-up period of 12.6 years, there was an overall increased incidence of skin cancer in those with increased dietary folate (P=.03). Furthermore, when striating by skin cancer type, there was an increased incidence of NMSC overall as well as BCC when analyzing by type of NMSC (P=.03 for NMSC; P=.05 for BCC). However, when stratifying by gender, these findings only held true for women.⁴¹ Similar effects were observed by Fung et al,⁴² who prospectively studied the intake of various vitamins in relationship to the development of BCC in women. During 12 years of follow-up, a positive association was observed between folate intake and BCC development (OR, 1.2; 95% CI, 1.10-1.31).⁴² Fung et al⁴³ also investigated the role of several vitamins in the development of SCC and found that folate showed a negative association, which did not reach statistical significance (RR, 0.79; 95% CI, 0.56-1.11). Furthermore, Vollset et al⁴⁰ conducted a meta-analysis comparing folic acid to placebo in the incidence of various types of cancer. The study excluded NMSC but reported no significant association between the development of melanoma and folic acid supplementation.⁴⁰ In summary, the effects of folate have diverse consequences, potentially promoting the formation of NMSC, but studies suggest that an individual’s gender and other genetic and environmental factors also may play a role.

Vitamin C—Vitamin C (also known as ascorbic acid) is a water-soluble vitamin with antioxidant immune-mediating effects. It is found in various fruits and vegetables and serves as a cofactor for enzymes within the body playing a key role in immune function and collagen formation.^44,45 It has been postulated that ascorbic acid can provide protection from UV radiation damage via its intracellular activity but conversely can contribute to oxidative damage.⁴⁴ Multiple in vitro laboratory studies and animal models have demonstrated photoprotective effects of ascorbic acid.^46-48 Despite these findings, minimal photoprotective effects have been found in the human population.

Kune et al⁴⁹ performed a case-control study of 88 males with previously diagnosed NMSC undergoing surgical removal and investigated patients’ prior dietary habits. Patients with NMSC had a statistically significantly lower level of vitamin C–containing food in their diet than those without NMSC (P=.004).⁴⁹ In addition, Vural et al⁵⁰ analyzed plasma samples and blood cells of patients with AK and BCC and found a significant decrease in ascorbic acid levels in both the AK (P<.001) and BCC (P<.001) groups compared with controls. However, studies have found that consumption of certain dietary compounds can rapidly increase plasma concentration levels, which may serve as a major confounding variable in this study. Plasma concentrations of ascorbic acid and beta carotene were found to be significantly increased following consumption of a high-antioxidant diet for as short a duration as 2 weeks (P<.05).⁵¹ More recently, Heinen et al⁵² performed a prospective study on 1001 adults. In patients without a history of skin cancer, they found that vitamin C from food sources plus dietary supplements was positively associated with the development of BCC (P=.03).⁵² Similarly, Fung et al⁴² performed a study in women and found a positive association between vitamin C intake and the development of BCC (OR, 1.13; 95% CI, 1.03-1.23).

The relationship between vitamin C intake—either in dietary or supplemental form—and melanoma remains controversial. Mice-based studies found that high concentrations of orally administered vitamin C induce cytotoxicity in melanoma cell lines, but at low concentrations they promote tumor growth of malignant melanoma.⁵³ Feskanich et al²³ examined the relationship between vitamin C intake and melanoma development via food frequency questionnaires in White women and found that vitamin C was associated with a higher risk for melanoma (P=.05), and furthermore, a positive dose response with frequency of orange juice intake was observed (P=.008). Overall, despite promising laboratory studies, there is a lack of RCTs investigating the use of vitamin C supplementation for prevention of NMSC and melanoma in humans, and the oral benefits of vitamin C for chemoprevention remain unclear.

Vitamin D—Vitamin D is a fat-soluble vitamin that is found in fish, liver, egg, and cheese, and is endogenously produced when UV radiation from sun exposure interacts with the skin, triggering the synthesis of vitamin D.⁵⁴ Vitamin D is biologically inactive and must be converted to its active form 1,25-dihydroxyvitamin D after entering the body. Vitamin D modulates many genes involved in cellular proliferation and differentiation.⁵⁴ Vitamin D receptors are expressed on keratinocytes and melanocytes.⁵⁵ Animal studies have demonstrated a potentially protective effect of vitamin D in the development of NMSC.⁵⁶ In a mouse model, Ellison et al⁵⁶ found that mice without vitamin D receptors developed skin tumors more rapidly than those with vitamin D receptors.

Unfortunately, these findings have not been demonstrated in humans, and studies have even reported an increased risk for development of NMSC in patients with normal or increased vitamin D levels compared with those with low levels of vitamin D.^57-60 Eide et al⁵⁷ studied 3223 patients seeking advice for low bone density by recording their vitamin D levels at the time of presentation and monitoring development of NMSC. Vitamin D levels greater than 15 ng/mL were positively associated with the development of NMSC (OR, 1.7; 95% CI, 1.04-2.7). This association held true for both SCC and BCC, with a higher risk estimated for SCC (OR, 3.2; 95% CI, 0.4-24.0 for SCC; OR, 1.7; 95% CI, 0.5-5.8 for BCC).⁵⁷ An increased vitamin D serum level also was found to be significantly associated with a higher risk for BCC and melanoma by van der Pols et al.⁵⁸ This prospective study looked at the incidence of skin cancer over 11 years. Study participants with vitamin D levels over 75 nmol/L more frequently developed BCC (P=.01) and melanoma (P=.05). In contrast, SCC was less frequently observed in participants with these high levels of vitamin D (P=.07).⁵⁸ Furthermore, Park et al⁶⁰ looked at vitamin D and skin cancer risk for men and women in the United States and found no association with risk for SCC or melanoma but a positive association with BCC (P=.05 for total vitamin D; P<.01 for dietary vitamin D). Additional studies have been performed with inconsistent results, and multiple authors suggest the possible confounding relationship between vitamin D levels and UV radiation exposure.^59-62 Furthermore, some studies have even demonstrated a negative association between vitamin D and NMSC. Tang et al⁶³ performed a retrospective case-control study in elderly males, investigating serum levels of vitamin D and patients’ self-reported history of NMSC, which demonstrated that higher levels of vitamin D were associated with a decreased risk for NMSC. Overall, the relationship between vitamin D and skin cancer development remains unclear for both melanoma and NMSC.

Vitamin E—Vitamin E is a fat-soluble vitamin that is found in plant-based oils, nuts, seeds, fruits, and vegetables.⁶⁴ It works as an antioxidant to protect against free radicals and heighten immune function, and it also serves as a pro-oxidant.^65,66 Vitamin E naturally exists in 8 chemical forms, of which gamma-tocopherol is the most frequently obtained form in the diet, and alpha-tocopherol is the most abundant form found in the body.^64,65

Early animal studies demonstrated the inhibition of UV-induced damage in mice receiving vitamin E supplementation.^67,68 Human studies have not consistently shown these effects. Vural et al⁵⁰ investigated plasma samples and blood cells of patients with AKs and BCCs and reported a significant decrease in alpha-tocopherol levels in both the AK (P<.05) and BCC (P<.001) groups compared with controls. However, studies also have demonstrated a positive association between vitamin E intake and the development of BCC, including one by Fung et al,⁴² which found a significant association in women (OR, 1.15; 95% CI, 1.06-1.26).

Vitamin E has been found to inhibit melanin synthesis in the laboratory, suggesting a potentially protective effect in melanoma.^69,70 However, in the study performed by Feskanich et al²³ examining vitamin intake and melanoma incidence via food-frequency questionnaires, vitamin E was not associated with a lower risk for melanoma. Despite promising laboratory studies, the data surrounding the use of a vitamin E supplement for prevention of melanoma and NMSC in humans remains unclear.

Selenium—Selenium is a trace mineral found in plants, meat, and fish. It plays a key role in reproduction, hormone metabolism, DNA synthesis, and protection from oxidative damage.⁷¹ In mice studies, lack of selenium-containing proteins resulted in skin abnormalities, including the development of a hyperplastic epidermis and aberrant hair follicle morphogenesis with alopecia after birth, and numerous experimental studies have demonstrated a negative association between selenium intake and cancer.^72,73 However, human studies have yielded alternative results. 

The Nutritional Prevention of Cancer Study Group analyzed 1312 dermatology patients with a history of NMSC.⁷⁴ The study population was obtained from 7 dermatology clinics with randomization to control for confounding variables. Study participants received either 200 μg of selenium daily or placebo.⁷⁴ Baseline characteristics of each study group were overall balanced. Selenium intake was found to have no effect on the development of BCC (hazard ratio [HR], 1.09; 95% CI, 0.94-1.26) but an increased risk for developing SCC (HR, 1.25; 95% CI, 1.03-1.51) and total NMSC (HR, 1.17; 95% CI, 1.02-1.34).^74,75 Similarly, Reid et al⁷⁶ performed an RCT comparing patients treated with 400 μg/d of selenium to those treated with 200 μg/d of selenium. When compared with placebo, those treated with 200 μg/d of selenium had a statistically significantly increased incidence of NMSC (P=.006); however, those treated with 400 μg/d of selenium had no significant change in total incidence of NMSC (P=.51).⁷⁶ Furthermore, Vinceti et al⁷⁷ performed a review of 83 studies from the literature investigating the effect of dietary selenium, and from the RCTs, there was no beneficial effect of selenium in reducing cancer risk in general; however, some studies demonstrated an increased incidence of other types of cancer, including melanoma. Of the RCTs included in the study investigating NMSC incidence specifically, it was found that the incidence was not affected by selenium administration (RR, 1.16; 95% CI, 0.30-4.42; 2 studies, 2027 participants).⁷⁷ Despite data from several studies demonstrating an increased risk for NMSC, the effects of selenium on the risk for NMSC and melanoma remain unclear. 

Combination Antioxidant Studies

In addition to investigating the use of single antioxidants in skin cancer prevention, studies utilizing the combination of various antioxidants or other dietary minerals have been conducted. Hercberg et al⁷⁸ performed a randomized, double-blinded, placebo-controlled trial of 13,017 adults (7876 women and 5141 men) receiving a combination of 120 mg vitamin C, 30 mg vitamin E, 100 μg selenium, 6 mg beta carotene, and 20 mg zinc. Study participants were followed for an average of 7.5 years, and the development of skin cancers were recorded. Overall, the incidence rate of skin cancer did not differ between the 2 treatment groups; however, when segregated by gender, the study found that there was an increased risk for developing skin cancer in women taking the antioxidant supplement combination compared with placebo (P=.03). This difference was not observed in the 2 treatment groups of male patients (P=.11). When looking specifically at NMSC, there was no difference between treatment groups for male or female patients (P=.39 for males; P=.15 for females). In contrast, there was a higher incidence of melanoma identified in female patients taking the combination antioxidant supplement (P=.01), but this was not seen within the male study population (P=.51).⁷⁸ In addition, Chang et al⁷⁹ performed a meta-analysis of 10 previously published RCTs. Analysis revealed that treatment with a variety of supplements, including vitamins A, C, E, and beta carotene, were found to have no preventative effects on the incidence of skin cancer development (RR, 0.98; CI, 0.98-1.03). Notable limitations to this study included the variability in protocols of the studies included in this meta-analysis, the limited number of RCTs investigating vitamin supplementation and the risk for skin cancer development, and the influence of dietary intake on study outcomes.⁷⁹

Other Dietary Agents

Furocoumarins—Furocoumarins are botanical substances found in various fruits and plants, including many citrus products. Furocoumarins are activated by UV light radiation and can lead to development of a phototoxic eruption. Several studies have suggested a pharmacogenetic effect of furocoumarins.⁸⁰ Sun et al⁸⁰ collected dietary data from 47,453 men and 75,291 women on furocoumarin intake and correlation with the development of NMSC. Overall, the study suggested that the intake of furocoumarins may lead to an increase in the development of BCC (HR, 1.16; 95% CI, 1.11-1.21; P=.002); however, there was no significant association identified between total intake of furocoumarins in the risk for SCC or melanoma.⁸⁰ Furthermore, Sakaki et al⁸¹ conducted a survey study looking at the consumption of citrus products and the development of NMSC. The group found that there was an increased risk for NMSC in those consuming an increased amount of citrus products (P=.007).⁸¹

Conclusion

Dietary antioxidants have been investigated for their potential role in the prevention of tumorigenesis. Specific antioxidant vitamins, such as vitamin A derivatives and niacinamide, have demonstrated clinical utility in the prevention of NMSC in high-risk populations. Retinol also has been associated with a reduced incidence of melanoma. Numerous antioxidants have demonstrated promising data within the laboratory setting; however, inconsistent results have been appreciated in humans. Furthermore, several research studies suggest that folate, vitamin D, and furocoumarins may be associated with an increased risk for skin cancer development; however, these studies are inconclusive, and dietary studies are challenging to conduct. Overall, RCTs investigating the role of antioxidants for chemoprevention are limited. Moreover, the study of dietary antioxidants and vitamins may be affected by various confounding variables that can be difficult to account for because of patients’ potentially poor recall of dietary intake and the effect of dietary intake in supplemental studies. Given the increasing prevalence of skin cancer worldwide, further research into the clinical utility of antioxidants in skin cancer prevention is warranted. 

Nonmelanoma skin cancer (NMSC) is the most common cancer in the United States, and cutaneous melanoma is projected to be the fifth most common form of cancer in 2022, with increasing incidence and high potential for mortality.^1-3 Estimates indicate that 35% to 45% of all cancers in White patients are cutaneous, with 4% to 5% occurring in Hispanic patients, 2% to 4% in Asian patients, and 1% to 2% in Black patients.⁴ Of the keratinocyte carcinomas, basal cell carcinoma (BCC) is the most prevalent, projected to affect approximately 33% to 39% of White males and 23% to 28% of White females in the United States during their lifetimes. Squamous cell carcinoma (SCC) is the second most common skin malignancy, with a lifetime risk of 9% to 14% for White males and 4% to 9% for White females in the United States.⁵ The incidence of melanoma continues to increase, with approximately 99,780 new cases expected in the United States in 2022.¹

UV-induced DNA damage plays a key role in the pathogenesis and development of various skin malignancies.⁶ UV radiation from sunlight or tanning devices causes photocarcinogenesis due to molecular and cellular effects, including the generation of reactive oxygen species, DNA damage due to the formation of cyclobutane pyrimidine dimers and pyrimidine-pyrimidone, melanogenesis, apoptosis, and the increased expression of harmful genes and proteins.⁶ The summation of this damage can result in skin malignancies, including NMSC and melanoma.^6,7 Dietary antioxidants theoretically help prevent oxidative reactions from occurring within the body, and it has been suggested that intake of dietary antioxidants may decrease DNA damage and prevent tumorigenesis secondary to UV radiation.⁸ Antioxidants exist naturally in the body but can be acquired exogenously. Investigators have studied dietary antioxidants in preventing skin cancer formation with promising results in the laboratory setting.^8-11 Recently, more robust human studies have been initiated to further delineate this relationship. We present clinical evidence of several frequently utilized antioxidant vitamins and their effects on melanoma and NMSC.

Antioxidants

Vitamin A—Vitamin A is a fat-soluble vitamin found in animal sources, including fish, liver, and eggs. Carotenoids, such as beta carotene, are provitamin A plant derivatives found in fruits and vegetables that are converted into biologically active retinol and retinoic acid.¹² Retinols play a key role in cellular growth and differentiation and are thought to be protective against skin cancer via the inactivation of free radicals and immunologic enhancement due to their antiproliferative, antioxidative, and antiapoptotic effects.^13-16 Animal studies have demonstrated this protective effect and the ability of retinoids to suppress carcinogenesis; however, human studies reveal conflicting results.^17,18

Greenberg et al¹⁹ investigated the use of beta carotene in preventing the formation of NMSC. Patients (N=1805) were randomized to receive 50 mg of beta carotene daily or placebo. Over a 5-year period, there was no significant reduction in the occurrence of NMSC (relative risk [RR], 1.05; 95% CI, 0.91-1.22).¹⁹ Frieling et al²⁰ conducted a similar randomized, double-blind, placebo-controlled trial investigating beta carotene for primary prevention of NMSC in 22,071 healthy male physicians. The study group received 50 mg of beta carotene every other day for 12 years’ duration, and there was no significant effect on the incidence of first NMSC development (RR, 0.98; 95% CI, 0.92-1.05).²⁰

A case-control study by Naldi et al²¹ found an inverse association between vitamin A intake and development of melanoma. Study participants were stratified into quartiles based on level of dietary intake and found an odds ratio (OR) of 0.71 for beta carotene (95% CI, 0.50-1.02), 0.57 for retinol (95% CI, 0.39-0.83), and 0.51 for total vitamin A (95% CI, 0.35-0.75) when comparing the upper quartile of vitamin A intake to the lower quartile. Upper-quartile cutoff values of vitamin A intake were 214 µg/d for beta carotene, 149 µg/d for retinol, and 359 µg/d for total vitamin A.²¹ More recently, a meta-analysis by Zhang et al²² pooled data from 8 case-control studies and 2 prospective studies. Intake of retinol but not total vitamin A or beta carotene was associated with a reduced risk for development of melanoma (retinol: OR, 0.80; 95% CI, 0.69-0.92; total vitamin A: OR, 0.86; 95% CI, 0.59-1.25; beta carotene: OR, 0.87; 95% CI, 0.62-1.20).²² Feskanich et al²³ demonstrated similar findings with use of food-frequency questionnaires in White women, suggesting that retinol intake from food combined with supplements may be protective for women who were otherwise at a low risk for melanoma based on nondietary factors. These factors included painful or blistering sunburns during childhood, history of more than 6 sunburns, more than 3 moles on the left arm, having red or blonde hair, and having a parent or sibling with melanoma (P=.01). However, this relationship did not hold true when looking at women at an intermediate or high risk for melanoma (P=.16 and P=.46).²³

When looking at high-risk patients, such as transplant patients, oral retinoids have been beneficial in preventing NMSC.^24-27 Bavinck et al²⁴ investigated 44 renal transplant patients with a history of more than 10 NMSCs treated with 30 mg of acitretin daily vs placebo. Patients receiving oral retinoid supplementation developed fewer NMSCs over a 6-month treatment period (P=.01).²⁴ Similarly, George et al²⁵ investigated acitretin in renal transplant patients and found a statistically significant decrease in number of SCCs in patients on supplementation (P=.002). Solomon-Cohen et al²⁶ performed a retrospective case-crossover study in solid organ transplant recipients and found that those treated with 10 mg of acitretin daily for 2 years had a significant reduction in the number of new keratinocyte carcinomas (P=.002). Other investigators have demonstrated similar results, and in 2006, Otley et al²⁷ proposed standardized dosing of acitretin for chemoprevention in high-risk patients, including patients developing 5 to 10 NMSCs per year, solid organ transplant recipients, and those with syndromes associated with the development of NMSC.^28,29 Overall, in the general population, vitamin A and related compounds have not demonstrated a significant association with decreased development of NMSC; however, oral retinoids have proven useful for high-risk patients. Furthermore, several studies have suggested a negative association between vitamin A levels and the incidence of melanoma, specifically in the retinol formulation. 

Vitamin B₃—Nicotinamide (also known as niacinamide) is a water-soluble form of vitamin B₃ and is obtained from animal-based and plant-based foods, such as meat, fish, and legumes.³⁰ Nicotinamide plays a key role in cellular metabolism, cellular signaling, and DNA repair, including protection from UV damage within keratinocytes.^31,32 Early mouse models demonstrated decreased formation of skin tumors in mice treated with topical or oral nicotinamide.^32,33 A number of human studies have revealed similar results.^34-36

Chen et al³⁴ conducted the ONTRAC study, a phase 3, double-blind, randomized controlled trial (RCT) looking at 386 participants with a history of at least 2 NMSCs in the preceding 5 years. At 12 months, those treated with 500 mg of nicotinamide twice daily demonstrated a statistically significant decreased rate of SCC formation (P=.05). A decreased incidence of BCC development was noted; however, this trend did not reach statistical significance (P=.12). Precancerous skin lesions also were found to be decreased in the treatment group, with 20% lower incidence of actinic keratoses (AKs) after 9 months of treatment (P<.001).³⁴ Drago et al³⁵ specifically studied the incidence of AKs in 38 transplant recipients—8 liver and 30 kidney—and found that previously noted AKs had decreased in size for 18 of 19 patients taking 500 mg of nicotinamide daily when originally photographed AKs were remeasured at 6-month follow-up, with 7 of these 18 patients demonstrating complete clinical regression. Of those on nicotinamide supplementation, no new AKs developed compared to the control group, which demonstrated increased size of AKs or development of new AKs in 91% of patients, with 7 AKs progressing into SCC.³⁵

Nicotinamide has been demonstrated to be useful in preventing skin cancer in high-risk populations, such as transplant patients or those with a high incidence of NMSC.^34,36 Despite promising results within the laboratory setting, nicotinamide’s effects on melanoma in humans remains less clear.^31,37 Studies suggest that nicotinamide enhances tumor-infiltrating lymphocytes and DNA repair mechanisms in melanocytes, which may translate into nicotinamide, providing chemoprevention for melanoma, but research in human patients is limited.^31,37

Vitamin B₉—Folate, the natural form of vitamin B₉, is a water-soluble compound that is found in many foods, especially green leafy vegetables, and often is supplemented because of its health benefits.^38,39 In the skin, folic acid plays a key role in cellular replication and proliferation.³⁸ Controversy exists regarding folate’s effects on cellular growth and turnover with respect to cancer incidence.^38,40 Donnenfeld et al⁴¹ conducted a prospective study assessing dietary folic acid intake and development of NMSC. A total of 5880 participants completed dietary records throughout the first 2 years of the study. After an average follow-up period of 12.6 years, there was an overall increased incidence of skin cancer in those with increased dietary folate (P=.03). Furthermore, when striating by skin cancer type, there was an increased incidence of NMSC overall as well as BCC when analyzing by type of NMSC (P=.03 for NMSC; P=.05 for BCC). However, when stratifying by gender, these findings only held true for women.⁴¹ Similar effects were observed by Fung et al,⁴² who prospectively studied the intake of various vitamins in relationship to the development of BCC in women. During 12 years of follow-up, a positive association was observed between folate intake and BCC development (OR, 1.2; 95% CI, 1.10-1.31).⁴² Fung et al⁴³ also investigated the role of several vitamins in the development of SCC and found that folate showed a negative association, which did not reach statistical significance (RR, 0.79; 95% CI, 0.56-1.11). Furthermore, Vollset et al⁴⁰ conducted a meta-analysis comparing folic acid to placebo in the incidence of various types of cancer. The study excluded NMSC but reported no significant association between the development of melanoma and folic acid supplementation.⁴⁰ In summary, the effects of folate have diverse consequences, potentially promoting the formation of NMSC, but studies suggest that an individual’s gender and other genetic and environmental factors also may play a role.

Vitamin C—Vitamin C (also known as ascorbic acid) is a water-soluble vitamin with antioxidant immune-mediating effects. It is found in various fruits and vegetables and serves as a cofactor for enzymes within the body playing a key role in immune function and collagen formation.^44,45 It has been postulated that ascorbic acid can provide protection from UV radiation damage via its intracellular activity but conversely can contribute to oxidative damage.⁴⁴ Multiple in vitro laboratory studies and animal models have demonstrated photoprotective effects of ascorbic acid.^46-48 Despite these findings, minimal photoprotective effects have been found in the human population.

Kune et al⁴⁹ performed a case-control study of 88 males with previously diagnosed NMSC undergoing surgical removal and investigated patients’ prior dietary habits. Patients with NMSC had a statistically significantly lower level of vitamin C–containing food in their diet than those without NMSC (P=.004).⁴⁹ In addition, Vural et al⁵⁰ analyzed plasma samples and blood cells of patients with AK and BCC and found a significant decrease in ascorbic acid levels in both the AK (P<.001) and BCC (P<.001) groups compared with controls. However, studies have found that consumption of certain dietary compounds can rapidly increase plasma concentration levels, which may serve as a major confounding variable in this study. Plasma concentrations of ascorbic acid and beta carotene were found to be significantly increased following consumption of a high-antioxidant diet for as short a duration as 2 weeks (P<.05).⁵¹ More recently, Heinen et al⁵² performed a prospective study on 1001 adults. In patients without a history of skin cancer, they found that vitamin C from food sources plus dietary supplements was positively associated with the development of BCC (P=.03).⁵² Similarly, Fung et al⁴² performed a study in women and found a positive association between vitamin C intake and the development of BCC (OR, 1.13; 95% CI, 1.03-1.23).

The relationship between vitamin C intake—either in dietary or supplemental form—and melanoma remains controversial. Mice-based studies found that high concentrations of orally administered vitamin C induce cytotoxicity in melanoma cell lines, but at low concentrations they promote tumor growth of malignant melanoma.⁵³ Feskanich et al²³ examined the relationship between vitamin C intake and melanoma development via food frequency questionnaires in White women and found that vitamin C was associated with a higher risk for melanoma (P=.05), and furthermore, a positive dose response with frequency of orange juice intake was observed (P=.008). Overall, despite promising laboratory studies, there is a lack of RCTs investigating the use of vitamin C supplementation for prevention of NMSC and melanoma in humans, and the oral benefits of vitamin C for chemoprevention remain unclear.

Vitamin D—Vitamin D is a fat-soluble vitamin that is found in fish, liver, egg, and cheese, and is endogenously produced when UV radiation from sun exposure interacts with the skin, triggering the synthesis of vitamin D.⁵⁴ Vitamin D is biologically inactive and must be converted to its active form 1,25-dihydroxyvitamin D after entering the body. Vitamin D modulates many genes involved in cellular proliferation and differentiation.⁵⁴ Vitamin D receptors are expressed on keratinocytes and melanocytes.⁵⁵ Animal studies have demonstrated a potentially protective effect of vitamin D in the development of NMSC.⁵⁶ In a mouse model, Ellison et al⁵⁶ found that mice without vitamin D receptors developed skin tumors more rapidly than those with vitamin D receptors.

Unfortunately, these findings have not been demonstrated in humans, and studies have even reported an increased risk for development of NMSC in patients with normal or increased vitamin D levels compared with those with low levels of vitamin D.^57-60 Eide et al⁵⁷ studied 3223 patients seeking advice for low bone density by recording their vitamin D levels at the time of presentation and monitoring development of NMSC. Vitamin D levels greater than 15 ng/mL were positively associated with the development of NMSC (OR, 1.7; 95% CI, 1.04-2.7). This association held true for both SCC and BCC, with a higher risk estimated for SCC (OR, 3.2; 95% CI, 0.4-24.0 for SCC; OR, 1.7; 95% CI, 0.5-5.8 for BCC).⁵⁷ An increased vitamin D serum level also was found to be significantly associated with a higher risk for BCC and melanoma by van der Pols et al.⁵⁸ This prospective study looked at the incidence of skin cancer over 11 years. Study participants with vitamin D levels over 75 nmol/L more frequently developed BCC (P=.01) and melanoma (P=.05). In contrast, SCC was less frequently observed in participants with these high levels of vitamin D (P=.07).⁵⁸ Furthermore, Park et al⁶⁰ looked at vitamin D and skin cancer risk for men and women in the United States and found no association with risk for SCC or melanoma but a positive association with BCC (P=.05 for total vitamin D; P<.01 for dietary vitamin D). Additional studies have been performed with inconsistent results, and multiple authors suggest the possible confounding relationship between vitamin D levels and UV radiation exposure.^59-62 Furthermore, some studies have even demonstrated a negative association between vitamin D and NMSC. Tang et al⁶³ performed a retrospective case-control study in elderly males, investigating serum levels of vitamin D and patients’ self-reported history of NMSC, which demonstrated that higher levels of vitamin D were associated with a decreased risk for NMSC. Overall, the relationship between vitamin D and skin cancer development remains unclear for both melanoma and NMSC.

Vitamin E—Vitamin E is a fat-soluble vitamin that is found in plant-based oils, nuts, seeds, fruits, and vegetables.⁶⁴ It works as an antioxidant to protect against free radicals and heighten immune function, and it also serves as a pro-oxidant.^65,66 Vitamin E naturally exists in 8 chemical forms, of which gamma-tocopherol is the most frequently obtained form in the diet, and alpha-tocopherol is the most abundant form found in the body.^64,65

Early animal studies demonstrated the inhibition of UV-induced damage in mice receiving vitamin E supplementation.^67,68 Human studies have not consistently shown these effects. Vural et al⁵⁰ investigated plasma samples and blood cells of patients with AKs and BCCs and reported a significant decrease in alpha-tocopherol levels in both the AK (P<.05) and BCC (P<.001) groups compared with controls. However, studies also have demonstrated a positive association between vitamin E intake and the development of BCC, including one by Fung et al,⁴² which found a significant association in women (OR, 1.15; 95% CI, 1.06-1.26).

Vitamin E has been found to inhibit melanin synthesis in the laboratory, suggesting a potentially protective effect in melanoma.^69,70 However, in the study performed by Feskanich et al²³ examining vitamin intake and melanoma incidence via food-frequency questionnaires, vitamin E was not associated with a lower risk for melanoma. Despite promising laboratory studies, the data surrounding the use of a vitamin E supplement for prevention of melanoma and NMSC in humans remains unclear.

Selenium—Selenium is a trace mineral found in plants, meat, and fish. It plays a key role in reproduction, hormone metabolism, DNA synthesis, and protection from oxidative damage.⁷¹ In mice studies, lack of selenium-containing proteins resulted in skin abnormalities, including the development of a hyperplastic epidermis and aberrant hair follicle morphogenesis with alopecia after birth, and numerous experimental studies have demonstrated a negative association between selenium intake and cancer.^72,73 However, human studies have yielded alternative results. 

The Nutritional Prevention of Cancer Study Group analyzed 1312 dermatology patients with a history of NMSC.⁷⁴ The study population was obtained from 7 dermatology clinics with randomization to control for confounding variables. Study participants received either 200 μg of selenium daily or placebo.⁷⁴ Baseline characteristics of each study group were overall balanced. Selenium intake was found to have no effect on the development of BCC (hazard ratio [HR], 1.09; 95% CI, 0.94-1.26) but an increased risk for developing SCC (HR, 1.25; 95% CI, 1.03-1.51) and total NMSC (HR, 1.17; 95% CI, 1.02-1.34).^74,75 Similarly, Reid et al⁷⁶ performed an RCT comparing patients treated with 400 μg/d of selenium to those treated with 200 μg/d of selenium. When compared with placebo, those treated with 200 μg/d of selenium had a statistically significantly increased incidence of NMSC (P=.006); however, those treated with 400 μg/d of selenium had no significant change in total incidence of NMSC (P=.51).⁷⁶ Furthermore, Vinceti et al⁷⁷ performed a review of 83 studies from the literature investigating the effect of dietary selenium, and from the RCTs, there was no beneficial effect of selenium in reducing cancer risk in general; however, some studies demonstrated an increased incidence of other types of cancer, including melanoma. Of the RCTs included in the study investigating NMSC incidence specifically, it was found that the incidence was not affected by selenium administration (RR, 1.16; 95% CI, 0.30-4.42; 2 studies, 2027 participants).⁷⁷ Despite data from several studies demonstrating an increased risk for NMSC, the effects of selenium on the risk for NMSC and melanoma remain unclear. 

Combination Antioxidant Studies

In addition to investigating the use of single antioxidants in skin cancer prevention, studies utilizing the combination of various antioxidants or other dietary minerals have been conducted. Hercberg et al⁷⁸ performed a randomized, double-blinded, placebo-controlled trial of 13,017 adults (7876 women and 5141 men) receiving a combination of 120 mg vitamin C, 30 mg vitamin E, 100 μg selenium, 6 mg beta carotene, and 20 mg zinc. Study participants were followed for an average of 7.5 years, and the development of skin cancers were recorded. Overall, the incidence rate of skin cancer did not differ between the 2 treatment groups; however, when segregated by gender, the study found that there was an increased risk for developing skin cancer in women taking the antioxidant supplement combination compared with placebo (P=.03). This difference was not observed in the 2 treatment groups of male patients (P=.11). When looking specifically at NMSC, there was no difference between treatment groups for male or female patients (P=.39 for males; P=.15 for females). In contrast, there was a higher incidence of melanoma identified in female patients taking the combination antioxidant supplement (P=.01), but this was not seen within the male study population (P=.51).⁷⁸ In addition, Chang et al⁷⁹ performed a meta-analysis of 10 previously published RCTs. Analysis revealed that treatment with a variety of supplements, including vitamins A, C, E, and beta carotene, were found to have no preventative effects on the incidence of skin cancer development (RR, 0.98; CI, 0.98-1.03). Notable limitations to this study included the variability in protocols of the studies included in this meta-analysis, the limited number of RCTs investigating vitamin supplementation and the risk for skin cancer development, and the influence of dietary intake on study outcomes.⁷⁹

Other Dietary Agents

Furocoumarins—Furocoumarins are botanical substances found in various fruits and plants, including many citrus products. Furocoumarins are activated by UV light radiation and can lead to development of a phototoxic eruption. Several studies have suggested a pharmacogenetic effect of furocoumarins.⁸⁰ Sun et al⁸⁰ collected dietary data from 47,453 men and 75,291 women on furocoumarin intake and correlation with the development of NMSC. Overall, the study suggested that the intake of furocoumarins may lead to an increase in the development of BCC (HR, 1.16; 95% CI, 1.11-1.21; P=.002); however, there was no significant association identified between total intake of furocoumarins in the risk for SCC or melanoma.⁸⁰ Furthermore, Sakaki et al⁸¹ conducted a survey study looking at the consumption of citrus products and the development of NMSC. The group found that there was an increased risk for NMSC in those consuming an increased amount of citrus products (P=.007).⁸¹

Conclusion

Dietary antioxidants have been investigated for their potential role in the prevention of tumorigenesis. Specific antioxidant vitamins, such as vitamin A derivatives and niacinamide, have demonstrated clinical utility in the prevention of NMSC in high-risk populations. Retinol also has been associated with a reduced incidence of melanoma. Numerous antioxidants have demonstrated promising data within the laboratory setting; however, inconsistent results have been appreciated in humans. Furthermore, several research studies suggest that folate, vitamin D, and furocoumarins may be associated with an increased risk for skin cancer development; however, these studies are inconclusive, and dietary studies are challenging to conduct. Overall, RCTs investigating the role of antioxidants for chemoprevention are limited. Moreover, the study of dietary antioxidants and vitamins may be affected by various confounding variables that can be difficult to account for because of patients’ potentially poor recall of dietary intake and the effect of dietary intake in supplemental studies. Given the increasing prevalence of skin cancer worldwide, further research into the clinical utility of antioxidants in skin cancer prevention is warranted. 

Epidermal growth factor receptor (EGFR) inhibitors cause numerous cutaneous adverse events (AEs), including papulopustular eruptions, paronychia, acral fissures, xerosis, alopecia, and trichomegaly.¹ Symmetrical drug-related intertriginous and flexural exanthema (SDRIFE) is an uncommon type IV hypersensitivity reaction reported most commonly in association with β-lactam antibiotics and other medications.² Treatment of SDRIFE generally involves withdrawing the inciting medication; however, in SDRIFE secondary to oncologic therapies, medication withdrawal may not be feasible or desirable. We present 2 cases of SDRIFE secondary to EGFR inhibitors in which treatment was continued alongside supportive skin-directed therapies. We also review the literature.

Case Reports

Patient 1—A 65-year-old man with stage IV non–small cell lung cancer presented to the dermatology clinic with an eruption of 2 months’ duration that began in the periumbilical area and spread to the perianal area within 2 weeks of starting treatment with lazertinib and amivantamab. Physical examination was notable for Common Terminology Criteria for Adverse Events (CTCAE) Grade 2 periumbilical erythema and erosions as well as symmetric red-brown patches with linear erosions in the gluteal cleft (Figure 1) and Grade 2 facial papulopustular rash. Herpes simplex virus polymerase chain reaction and bacterial culture were negative. A skin biopsy from the left buttock revealed dermal edema and a perivascular lymphocytic infiltrate compatible with SDRIFE. Triamcinolone ointment 0.1% twice daily was initiated, then uptitrated to betamethasone ointment 0.05% twice daily with moderate improvement. The patient had a treatment interruption due to malignancy complications, at which time his skin improved, with recurrence of the eruption after treatment re-initiation. He resumed skin-directed treatment and was maintained on betamethasone ointment 0.05% and tacrolimus ointment 0.1% twice daily on alternating days. This treatment was continued for 4 months before the patient died from complications of the malignancy.

Patient 2—A 68-year-old woman with stage IV lung adenocarcinoma presented to the dermatology clinic with a rash of 3 weeks’ duration. Treatment with osimertinib was initiated 8 months prior to presentation, and there were no recent medication changes. Physical examination revealed CTCAE Grade 2 erythematous patches in the inguinal folds (Figure 2A), inframammary folds (Figure 2B), and on the nasal tip, as well as Grade 2 paronychia. The patient was managed with hydrocortisone cream 1% twice daily, and osimertinib was continued. At follow-up 4 weeks later, the erythema had faded to hyperpigmentation in affected areas with resolution of symptoms. No further treatment was required.

Comment

Supportive oncodermatologists and dermatology hospitalists should be aware of SDRIFE as an uncommon but increasingly recognized cutaneous AE of EGFR inhibitors. Other cases of SDRIFE secondary to EGFR inhibition are described in the Table.^2-5 Although SDRIFE typically is treated by discontinuation of the offending agent, in all reported cases of EGFR inhibitor–associated SDRIFE the rash was CTCAE Grade 2, meaning that it did not interfere with instrumental activities of daily living. In 5 of 6 cases, EGFR therapy was continued while skin-directed therapies were used for symptom management.

Presentation of SDRIFE—Symmetrical drug-related intertriginous and flexural exanthema is characterized by a symmetric, sharply demarcated erythema in the inguinal, gluteal, or perianal area with at least 1 other flexural localization involved in the absence of systemic signs. It is observed most frequently at initial exposure or re-exposure to a medication. Onset typically is within a few hours to a few days after exposure to a medication.⁶ Interestingly, in this case series, half of reported SDRIFE cases developed 8 months or more after EGFR inhibitor initiation.

Pathophysiology of SDRIFE—The mechanism of SDRIFE has not been clearly elucidated; it generally is accepted to be a delayed-type hypersensitivity drug reaction, though other proposed pathophysiologic mechanisms for the distribution of SDRIFE include recall phenomenon or predisposing anatomic factors such as temperature, humidity, and apocrine or eccrine gland density.^6,7 Epidermal growth factor receptor plays a critical role in regulating differentiation and proliferation of epidermal keratinocytes, hair follicles, and the sweat gland apparatus. Additionally, it has been hypothesized that EGFR inhibitor use may affect the microflora of the skin and that EGFR inhibitors directly affect the immune system, as demonstrated in an experiment showing EGFR inhibitor–treated mice had enhanced skin inflammation and contact hypersensitivity responses.⁸ How these disparate mechanisms may interact to produce SDRIFE and the reason for the notably delayed presentation of SDRIFE in half of the cases we reviewed is not known. Other delayed cutaneous AEs of EGFR inhibitor therapy, such as paronychia, are thought to be secondary to development of skin fragility and decreased keratinocyte proliferation with secondary infection.¹ It is conceivable that a combination of proliferative, immunologic, and microbiome-related factors may each be playing a role in EGFR inhibitor–related SDRIFE.

Dermatology Inpatient Considerations—As seen in our cases, dermatologists can play a valuable role in diagnosing, grading, and managing cutaneous AEs associated with the administration of oncologic therapies. The array of cutaneous AEs has grown as cancer treatment options have expanded from conventional antimetabolite agents to kinase inhibitors and immune checkpoint inhibitors. Dermatologists may play an important role in differentiating the etiology of a skin finding (eg, infectious vs inflammatory) and can identify serious or dose-limiting reactions, such as Stevens-Johnson syndrome or drug reaction with eosinophilia and systemic symptoms (DRESS). If cutaneous AEs appear to occur secondary to administration of a chemotherapeutic agent, use of the National Cancer Institute CTCAE should be employed. For certain AEs (eg, alopecia, acneiform rashes, bullous dermatitis), specific grading has been developed based on a combination of body surface area involved, psychosocial impact, symptoms, and other associated morbidity.⁹

In management of chemotherapy-associated cutaneous AEs, dermatologists are likely to be the members of the health care team most comfortable with prescribing high-potency anti-inflammatory topical medications. Dermatologic consultation for management of cutaneous AEs has been shown to both reduce the need for systemic immunosuppression and limit interruptions in oncologic treatment.¹⁰

Conclusion

Epidermal growth factor receptor inhibitors commonly are prescribed for colorectal cancer, non–small cell lung cancer, and squamous cell carcinoma of the head and neck. They are associated with a variety of cutaneous AEs, including acneiform eruptions, paronychia, and xerosis, which rarely necessitate stopping EGFR inhibitor therapy. Our cases support an approach to managing EGFR inhibitor–related SDRIFE that does not involve discontinuation of the offending agent. Further studies are needed on the best supportive topical and systemic regimens for EGFR inhibitor–associated SDRIFE.

Epidermal growth factor receptor (EGFR) inhibitors cause numerous cutaneous adverse events (AEs), including papulopustular eruptions, paronychia, acral fissures, xerosis, alopecia, and trichomegaly.¹ Symmetrical drug-related intertriginous and flexural exanthema (SDRIFE) is an uncommon type IV hypersensitivity reaction reported most commonly in association with β-lactam antibiotics and other medications.² Treatment of SDRIFE generally involves withdrawing the inciting medication; however, in SDRIFE secondary to oncologic therapies, medication withdrawal may not be feasible or desirable. We present 2 cases of SDRIFE secondary to EGFR inhibitors in which treatment was continued alongside supportive skin-directed therapies. We also review the literature.

Case Reports

Patient 1—A 65-year-old man with stage IV non–small cell lung cancer presented to the dermatology clinic with an eruption of 2 months’ duration that began in the periumbilical area and spread to the perianal area within 2 weeks of starting treatment with lazertinib and amivantamab. Physical examination was notable for Common Terminology Criteria for Adverse Events (CTCAE) Grade 2 periumbilical erythema and erosions as well as symmetric red-brown patches with linear erosions in the gluteal cleft (Figure 1) and Grade 2 facial papulopustular rash. Herpes simplex virus polymerase chain reaction and bacterial culture were negative. A skin biopsy from the left buttock revealed dermal edema and a perivascular lymphocytic infiltrate compatible with SDRIFE. Triamcinolone ointment 0.1% twice daily was initiated, then uptitrated to betamethasone ointment 0.05% twice daily with moderate improvement. The patient had a treatment interruption due to malignancy complications, at which time his skin improved, with recurrence of the eruption after treatment re-initiation. He resumed skin-directed treatment and was maintained on betamethasone ointment 0.05% and tacrolimus ointment 0.1% twice daily on alternating days. This treatment was continued for 4 months before the patient died from complications of the malignancy.

Patient 2—A 68-year-old woman with stage IV lung adenocarcinoma presented to the dermatology clinic with a rash of 3 weeks’ duration. Treatment with osimertinib was initiated 8 months prior to presentation, and there were no recent medication changes. Physical examination revealed CTCAE Grade 2 erythematous patches in the inguinal folds (Figure 2A), inframammary folds (Figure 2B), and on the nasal tip, as well as Grade 2 paronychia. The patient was managed with hydrocortisone cream 1% twice daily, and osimertinib was continued. At follow-up 4 weeks later, the erythema had faded to hyperpigmentation in affected areas with resolution of symptoms. No further treatment was required.

Comment

Supportive oncodermatologists and dermatology hospitalists should be aware of SDRIFE as an uncommon but increasingly recognized cutaneous AE of EGFR inhibitors. Other cases of SDRIFE secondary to EGFR inhibition are described in the Table.^2-5 Although SDRIFE typically is treated by discontinuation of the offending agent, in all reported cases of EGFR inhibitor–associated SDRIFE the rash was CTCAE Grade 2, meaning that it did not interfere with instrumental activities of daily living. In 5 of 6 cases, EGFR therapy was continued while skin-directed therapies were used for symptom management.

Presentation of SDRIFE—Symmetrical drug-related intertriginous and flexural exanthema is characterized by a symmetric, sharply demarcated erythema in the inguinal, gluteal, or perianal area with at least 1 other flexural localization involved in the absence of systemic signs. It is observed most frequently at initial exposure or re-exposure to a medication. Onset typically is within a few hours to a few days after exposure to a medication.⁶ Interestingly, in this case series, half of reported SDRIFE cases developed 8 months or more after EGFR inhibitor initiation.

Pathophysiology of SDRIFE—The mechanism of SDRIFE has not been clearly elucidated; it generally is accepted to be a delayed-type hypersensitivity drug reaction, though other proposed pathophysiologic mechanisms for the distribution of SDRIFE include recall phenomenon or predisposing anatomic factors such as temperature, humidity, and apocrine or eccrine gland density.^6,7 Epidermal growth factor receptor plays a critical role in regulating differentiation and proliferation of epidermal keratinocytes, hair follicles, and the sweat gland apparatus. Additionally, it has been hypothesized that EGFR inhibitor use may affect the microflora of the skin and that EGFR inhibitors directly affect the immune system, as demonstrated in an experiment showing EGFR inhibitor–treated mice had enhanced skin inflammation and contact hypersensitivity responses.⁸ How these disparate mechanisms may interact to produce SDRIFE and the reason for the notably delayed presentation of SDRIFE in half of the cases we reviewed is not known. Other delayed cutaneous AEs of EGFR inhibitor therapy, such as paronychia, are thought to be secondary to development of skin fragility and decreased keratinocyte proliferation with secondary infection.¹ It is conceivable that a combination of proliferative, immunologic, and microbiome-related factors may each be playing a role in EGFR inhibitor–related SDRIFE.

Dermatology Inpatient Considerations—As seen in our cases, dermatologists can play a valuable role in diagnosing, grading, and managing cutaneous AEs associated with the administration of oncologic therapies. The array of cutaneous AEs has grown as cancer treatment options have expanded from conventional antimetabolite agents to kinase inhibitors and immune checkpoint inhibitors. Dermatologists may play an important role in differentiating the etiology of a skin finding (eg, infectious vs inflammatory) and can identify serious or dose-limiting reactions, such as Stevens-Johnson syndrome or drug reaction with eosinophilia and systemic symptoms (DRESS). If cutaneous AEs appear to occur secondary to administration of a chemotherapeutic agent, use of the National Cancer Institute CTCAE should be employed. For certain AEs (eg, alopecia, acneiform rashes, bullous dermatitis), specific grading has been developed based on a combination of body surface area involved, psychosocial impact, symptoms, and other associated morbidity.⁹

In management of chemotherapy-associated cutaneous AEs, dermatologists are likely to be the members of the health care team most comfortable with prescribing high-potency anti-inflammatory topical medications. Dermatologic consultation for management of cutaneous AEs has been shown to both reduce the need for systemic immunosuppression and limit interruptions in oncologic treatment.¹⁰

Conclusion

Epidermal growth factor receptor inhibitors commonly are prescribed for colorectal cancer, non–small cell lung cancer, and squamous cell carcinoma of the head and neck. They are associated with a variety of cutaneous AEs, including acneiform eruptions, paronychia, and xerosis, which rarely necessitate stopping EGFR inhibitor therapy. Our cases support an approach to managing EGFR inhibitor–related SDRIFE that does not involve discontinuation of the offending agent. Further studies are needed on the best supportive topical and systemic regimens for EGFR inhibitor–associated SDRIFE.

Epidermal growth factor receptor (EGFR) inhibitors cause numerous cutaneous adverse events (AEs), including papulopustular eruptions, paronychia, acral fissures, xerosis, alopecia, and trichomegaly.¹ Symmetrical drug-related intertriginous and flexural exanthema (SDRIFE) is an uncommon type IV hypersensitivity reaction reported most commonly in association with β-lactam antibiotics and other medications.² Treatment of SDRIFE generally involves withdrawing the inciting medication; however, in SDRIFE secondary to oncologic therapies, medication withdrawal may not be feasible or desirable. We present 2 cases of SDRIFE secondary to EGFR inhibitors in which treatment was continued alongside supportive skin-directed therapies. We also review the literature.

Case Reports

Patient 1—A 65-year-old man with stage IV non–small cell lung cancer presented to the dermatology clinic with an eruption of 2 months’ duration that began in the periumbilical area and spread to the perianal area within 2 weeks of starting treatment with lazertinib and amivantamab. Physical examination was notable for Common Terminology Criteria for Adverse Events (CTCAE) Grade 2 periumbilical erythema and erosions as well as symmetric red-brown patches with linear erosions in the gluteal cleft (Figure 1) and Grade 2 facial papulopustular rash. Herpes simplex virus polymerase chain reaction and bacterial culture were negative. A skin biopsy from the left buttock revealed dermal edema and a perivascular lymphocytic infiltrate compatible with SDRIFE. Triamcinolone ointment 0.1% twice daily was initiated, then uptitrated to betamethasone ointment 0.05% twice daily with moderate improvement. The patient had a treatment interruption due to malignancy complications, at which time his skin improved, with recurrence of the eruption after treatment re-initiation. He resumed skin-directed treatment and was maintained on betamethasone ointment 0.05% and tacrolimus ointment 0.1% twice daily on alternating days. This treatment was continued for 4 months before the patient died from complications of the malignancy.

Patient 2—A 68-year-old woman with stage IV lung adenocarcinoma presented to the dermatology clinic with a rash of 3 weeks’ duration. Treatment with osimertinib was initiated 8 months prior to presentation, and there were no recent medication changes. Physical examination revealed CTCAE Grade 2 erythematous patches in the inguinal folds (Figure 2A), inframammary folds (Figure 2B), and on the nasal tip, as well as Grade 2 paronychia. The patient was managed with hydrocortisone cream 1% twice daily, and osimertinib was continued. At follow-up 4 weeks later, the erythema had faded to hyperpigmentation in affected areas with resolution of symptoms. No further treatment was required.

Comment

Supportive oncodermatologists and dermatology hospitalists should be aware of SDRIFE as an uncommon but increasingly recognized cutaneous AE of EGFR inhibitors. Other cases of SDRIFE secondary to EGFR inhibition are described in the Table.^2-5 Although SDRIFE typically is treated by discontinuation of the offending agent, in all reported cases of EGFR inhibitor–associated SDRIFE the rash was CTCAE Grade 2, meaning that it did not interfere with instrumental activities of daily living. In 5 of 6 cases, EGFR therapy was continued while skin-directed therapies were used for symptom management.

Presentation of SDRIFE—Symmetrical drug-related intertriginous and flexural exanthema is characterized by a symmetric, sharply demarcated erythema in the inguinal, gluteal, or perianal area with at least 1 other flexural localization involved in the absence of systemic signs. It is observed most frequently at initial exposure or re-exposure to a medication. Onset typically is within a few hours to a few days after exposure to a medication.⁶ Interestingly, in this case series, half of reported SDRIFE cases developed 8 months or more after EGFR inhibitor initiation.

Pathophysiology of SDRIFE—The mechanism of SDRIFE has not been clearly elucidated; it generally is accepted to be a delayed-type hypersensitivity drug reaction, though other proposed pathophysiologic mechanisms for the distribution of SDRIFE include recall phenomenon or predisposing anatomic factors such as temperature, humidity, and apocrine or eccrine gland density.^6,7 Epidermal growth factor receptor plays a critical role in regulating differentiation and proliferation of epidermal keratinocytes, hair follicles, and the sweat gland apparatus. Additionally, it has been hypothesized that EGFR inhibitor use may affect the microflora of the skin and that EGFR inhibitors directly affect the immune system, as demonstrated in an experiment showing EGFR inhibitor–treated mice had enhanced skin inflammation and contact hypersensitivity responses.⁸ How these disparate mechanisms may interact to produce SDRIFE and the reason for the notably delayed presentation of SDRIFE in half of the cases we reviewed is not known. Other delayed cutaneous AEs of EGFR inhibitor therapy, such as paronychia, are thought to be secondary to development of skin fragility and decreased keratinocyte proliferation with secondary infection.¹ It is conceivable that a combination of proliferative, immunologic, and microbiome-related factors may each be playing a role in EGFR inhibitor–related SDRIFE.

Dermatology Inpatient Considerations—As seen in our cases, dermatologists can play a valuable role in diagnosing, grading, and managing cutaneous AEs associated with the administration of oncologic therapies. The array of cutaneous AEs has grown as cancer treatment options have expanded from conventional antimetabolite agents to kinase inhibitors and immune checkpoint inhibitors. Dermatologists may play an important role in differentiating the etiology of a skin finding (eg, infectious vs inflammatory) and can identify serious or dose-limiting reactions, such as Stevens-Johnson syndrome or drug reaction with eosinophilia and systemic symptoms (DRESS). If cutaneous AEs appear to occur secondary to administration of a chemotherapeutic agent, use of the National Cancer Institute CTCAE should be employed. For certain AEs (eg, alopecia, acneiform rashes, bullous dermatitis), specific grading has been developed based on a combination of body surface area involved, psychosocial impact, symptoms, and other associated morbidity.⁹

In management of chemotherapy-associated cutaneous AEs, dermatologists are likely to be the members of the health care team most comfortable with prescribing high-potency anti-inflammatory topical medications. Dermatologic consultation for management of cutaneous AEs has been shown to both reduce the need for systemic immunosuppression and limit interruptions in oncologic treatment.¹⁰

Conclusion

Epidermal growth factor receptor inhibitors commonly are prescribed for colorectal cancer, non–small cell lung cancer, and squamous cell carcinoma of the head and neck. They are associated with a variety of cutaneous AEs, including acneiform eruptions, paronychia, and xerosis, which rarely necessitate stopping EGFR inhibitor therapy. Our cases support an approach to managing EGFR inhibitor–related SDRIFE that does not involve discontinuation of the offending agent. Further studies are needed on the best supportive topical and systemic regimens for EGFR inhibitor–associated SDRIFE.