Nonmelanoma Skin Cancer

Squamoid eccrine ductal carcinoma (SEDC) is an aggressive underrecognized cutaneous malignancy of unknown etiology.¹ It is most likely to occur in sun-exposed areas of the body, most commonly the head and neck. Risk factors include male sex, increased age, and chronic immunosuppression.^1-4 Current reports suggest that SEDC is likely a high-grade subtype of squamous cell carcinoma (SCC) with a high risk for local recurrence (25%) and metastasis (13%).^1,3,5,6 There are as few as 56 cases of SEDC reported in the literature; however, the number of cases may be closer to 100 due to SEDC being classified as either adenosquamous carcinoma of the skin or ductal eccrine carcinoma with squamous differentiation.¹

Clinically, SEDC mimics keratinocyte carcinomas. Histologically, SEDC is biphasic, with a superficial portion resembling well-differentiated SCC and a deeply invasive portion having infiltrative irregular cords with ductal differentiation. Perineural invasion (PNI) frequently is present. Multiple connections to the overlying epidermis also can be seen, serving as a subtle clue to the diagnosis on broad superficial specimens.^1-3 Due to superficial sampling, approximately 50% of reported cases are misdiagnosed as SCC during the initial biopsy.⁴ The diagnosis of SEDC often is made during complete excision when deeper tissue is sampled. Establishing an accurate diagnosis is important given the more aggressive nature of SEDC compared with SCC and its proclivity for PNI.^1,3,6 The purpose of this review is to increase awareness of this underrecognized entity and describe the histologic findings that help distinguish SEDC from SCC.

Patient Chart Review

We reviewed chart notes as well as frozen and formalin-fixed paraffin-embedded tissue sections from all 5 patients diagnosed with SEDC at a single institution between November 2018 and May 2020. The mean age of patients was 81 years, and 4 were male. Four of the patients presented for MMS with a preoperative diagnosis of SCC per the original biopsy results. Only 1 patient had a preoperative diagnosis of SEDC. The details of each case are recorded in the Table. All tumors were greater than 2 cm in diameter on initial presentation, were located on the head, and clinically resembled keratinocyte carcinoma with either a nodular or plaquelike appearance (Figure 1).

Intraoperative histologic examination of the excised tissue revealed a biphasic pattern consisting of superficial SCC features overlying deeper dermal and subcutaneous infiltrative malignant ductal elements with gland formation in all 5 patients (Figures 2–4). Immunohistochemical staining with cytokeratin AE1/AE3 revealed thin strands of carcinoma in the mid to deeper dermis with squamous differentiation and eccrine ductal differentiation (Figure 5), thus confirming the diagnosis in all 5 patients.

Literature Review

A PubMed review of the literature using the search term squamoid eccrine ductal carcinoma resulted in 28 articles, 19 of which were included in the review based on inclusion criteria (original articles available in English, in full text, and pertained to SEDC). Our review yielded 56 cases of SEDC.^1-19 The mean age of patients with SEDC was 72 years. The number of male and female cases was 52% (29/56) and 48% (27/56), respectively. The most common location of SEDC was on the head or neck (71% [40/56]), followed by the extremities (19% [11/56]). Immunosuppression was noted in 9% (5/56) of cases. Wide local excision was the most commonly employed treatment modality (91% [51/56]), with MMS being used in 4 patients (7%). Adjuvant radiation was reported in 5% (3/56) of cases. Perineural invasion was reported in 34% (19/56) of cases. Recurrence was seen in 23% (13/56) of cases, with a mean time to recurrence of 10.4 months. Metastasis to regional lymph nodes was observed in 13% (7/56) of cases, with 7% (4/56) of those cases having distant metastases.

Comment

Squamoid eccrine ductal carcinoma was successfully treated with MMS in all 5 of the patients we reviewed. Recognition of a distinct biphasic pattern consisting of squamous differentiation superficially with epidermal connection overlying deeper dermal and subcutaneous infiltrative malignant ductal elements with gland formation should lead to consideration of this diagnosis. A thorough inspection for PNI also should be performed, as this finding was present in all of 5 cases and in 34% of reported cases in our literature review.

The differential diagnosis for SEDC includes SCC, metastatic adenocarcinoma with squamoid features, and eccrine tumors, including eccrine poroma, microcystic adnexal carcinoma (MAC), and porocarcinoma with squamous differentiation. The combination of histologic features with the immunoexpression profile of carcinoembryonic antigen (CEA), epithelial membrane antigen (EMA), cytokeratin (CK) 5/6, and p63 can effectively exclude the other entities in the differential and confirm the diagnosis of SEDC.^1,3,4 While the diagnosis of SEDC relies on the specific histologic features of multiple surface attachments and superficial squamoid changes with deep ductular elements, immunohistochemistry can nonetheless be adjunctive in difficult cases. Positive immunohistochemical staining for CEA and EMA can help to highlight and delineate true glandular elements, whereas CK5/6 highlights the overall contour of the tumor, displaying more clearly the multiple epidermal attachments and the subtle infiltrative nature of the deeper components of invasive cords and ducts. In addition, the combination of CK5/6 and p63 positivity supports the primary cutaneous nature of the lesion rather than metastatic adenocarcinoma.^13,20 Other markers of eccrine secretory coils, such as CK7, CAM5.2, and S100, also are sometimes used for confirmation, some of which can aid in distinction from noneccrine sweat gland differentiation, as CK7 and CAM5.2 are negative in both luminal and basal cells of the dermal duct while being positive within the secretory coil, and S100 protein is expressed within eccrine secretory coil but negative within the apocrine sweat glands.^2,4,21

The clinical findings from our chart review corroborated those reported in the literature. The mean age of SEDC in the 5 patients we reviewed was 81 years, and all cases presented on the head, consistent with the findings observed in the literature. Although 4 of our cases were male, there may not be a difference in risk based on sex as previously thought.¹ Our literature review revealed an almost equivalent percentage of male and female cases, with 52% being male.

Immunosuppression has been associated with an increased risk for SEDC. Our literature review revealed that approximately 9% (5/56) of cases occurred in immunosuppressed individuals. Two of these reported cases were in the setting of underlying chronic lymphocytic leukemia, 2 in individuals with a history of organ transplant, and 1 treated with azathioprine for myasthenia gravis.^2,4,10,12,13 Our chart review supported this correlation, as all 5 patients had a medical history potentially consistent with being in an immunocompromised state (Table). Notably, patient 5 represents a unique case of SEDC occurring in the setting of HIV. The patient had HIV for 33 years, with his most recent CD4⁺ count of 794 mm³ and HIV-1 RNA load of 35 copies/mL. Given that HIV-positive individuals may have more than a 2-fold increased risk of SCC, a greater degree of suspicion for SEDC should be maintained for these patients.^22,23

The etiology of SEDC is controversial but is thought to be either an SCC arising from eccrine glands or a variant of eccrine carcinoma with extensive squamoid differentiation.^{4,6,13,14,17,24} While SEDC certainly appears to share the proclivity for PNI with the malignant eccrine tumor MAC, it is simultaneously quite distinct, demonstrating nuclear pleomorphism and mitotic activity, both of which are lacking in the bland nature of MACs.^12,25

The exact prevalence of SEDC is difficult to ascertain because of its frequent misdiagnosis and variable nomenclature used within the literature. Most reported cases of SEDC are mistakenly diagnosed as SCC on the initial shave or punch biopsy because of superficial sampling. This also was the case in 4 of the patients we reviewed. In addition, there are reported cases of SEDC that were referred to by the investigators as cutaneous adenosquamous carcinoma (cASC), among other descriptors, such as ductal eccrine carcinoma with squamous differentiation, adnexal carcinoma with squamous and ductal differentiation, and syringoid eccrine carcinoma.^26-32 While the World Health Organization classifies SEDC as a distinct variant of cASC, which is a rare variant of SCC in itself, the 2 can be differentiated. Despite the similar clinical and histologic features shared between cASC and SEDC, the neoplastic aggregates in SEDC exhibit ductal differentiation containing lumina positive for CEA and EMA.⁴ Overall, we favor the term squamoid eccrine ductal carcinoma, as there has recently been more uniformity for the designation of this disease entity as such.

It is unclear whether the high incidence of local recurrence (23% [13/56]) of SEDC reported in the literature is related to the treatment modality employed (ie, wide local excision) or due to the innate aggressiveness of SEDC.^1,3,5 The literature has shown that MMS has lower recurrence rates than other treatments at 5-year follow-up for SCC (3.1%–5%) and eccrine carcinomas (0%–5%).^33,34 Although studies assessing tumor behavior or comparing treatment modalities are limited because of the rarity and underrecognition of SEDC, MMS has been used several times for SEDC with only 1 recurrence reported.^4,13,17,24 Given that all 5 of the patients we reviewed required more than 1 Mohs stage for complete tumor clearance and none demonstrated evidence of recurrence or metastasis (Table), we recommend MMS as the treatment of choice for SEDC.

Conclusion

Squamoid eccrine ductal carcinoma is a rare but likely underdiagnosed cutaneous tumor of uncertain etiology. Because of its propensity for recurrence and metastasis, excision of SEDC with complete circumferential peripheral and deep margin assessment with close follow-up is recommended.

Squamoid eccrine ductal carcinoma (SEDC) is an aggressive underrecognized cutaneous malignancy of unknown etiology.¹ It is most likely to occur in sun-exposed areas of the body, most commonly the head and neck. Risk factors include male sex, increased age, and chronic immunosuppression.^1-4 Current reports suggest that SEDC is likely a high-grade subtype of squamous cell carcinoma (SCC) with a high risk for local recurrence (25%) and metastasis (13%).^1,3,5,6 There are as few as 56 cases of SEDC reported in the literature; however, the number of cases may be closer to 100 due to SEDC being classified as either adenosquamous carcinoma of the skin or ductal eccrine carcinoma with squamous differentiation.¹

Clinically, SEDC mimics keratinocyte carcinomas. Histologically, SEDC is biphasic, with a superficial portion resembling well-differentiated SCC and a deeply invasive portion having infiltrative irregular cords with ductal differentiation. Perineural invasion (PNI) frequently is present. Multiple connections to the overlying epidermis also can be seen, serving as a subtle clue to the diagnosis on broad superficial specimens.^1-3 Due to superficial sampling, approximately 50% of reported cases are misdiagnosed as SCC during the initial biopsy.⁴ The diagnosis of SEDC often is made during complete excision when deeper tissue is sampled. Establishing an accurate diagnosis is important given the more aggressive nature of SEDC compared with SCC and its proclivity for PNI.^1,3,6 The purpose of this review is to increase awareness of this underrecognized entity and describe the histologic findings that help distinguish SEDC from SCC.

Patient Chart Review

We reviewed chart notes as well as frozen and formalin-fixed paraffin-embedded tissue sections from all 5 patients diagnosed with SEDC at a single institution between November 2018 and May 2020. The mean age of patients was 81 years, and 4 were male. Four of the patients presented for MMS with a preoperative diagnosis of SCC per the original biopsy results. Only 1 patient had a preoperative diagnosis of SEDC. The details of each case are recorded in the Table. All tumors were greater than 2 cm in diameter on initial presentation, were located on the head, and clinically resembled keratinocyte carcinoma with either a nodular or plaquelike appearance (Figure 1).

Intraoperative histologic examination of the excised tissue revealed a biphasic pattern consisting of superficial SCC features overlying deeper dermal and subcutaneous infiltrative malignant ductal elements with gland formation in all 5 patients (Figures 2–4). Immunohistochemical staining with cytokeratin AE1/AE3 revealed thin strands of carcinoma in the mid to deeper dermis with squamous differentiation and eccrine ductal differentiation (Figure 5), thus confirming the diagnosis in all 5 patients.

Literature Review

A PubMed review of the literature using the search term squamoid eccrine ductal carcinoma resulted in 28 articles, 19 of which were included in the review based on inclusion criteria (original articles available in English, in full text, and pertained to SEDC). Our review yielded 56 cases of SEDC.^1-19 The mean age of patients with SEDC was 72 years. The number of male and female cases was 52% (29/56) and 48% (27/56), respectively. The most common location of SEDC was on the head or neck (71% [40/56]), followed by the extremities (19% [11/56]). Immunosuppression was noted in 9% (5/56) of cases. Wide local excision was the most commonly employed treatment modality (91% [51/56]), with MMS being used in 4 patients (7%). Adjuvant radiation was reported in 5% (3/56) of cases. Perineural invasion was reported in 34% (19/56) of cases. Recurrence was seen in 23% (13/56) of cases, with a mean time to recurrence of 10.4 months. Metastasis to regional lymph nodes was observed in 13% (7/56) of cases, with 7% (4/56) of those cases having distant metastases.

Comment

Squamoid eccrine ductal carcinoma was successfully treated with MMS in all 5 of the patients we reviewed. Recognition of a distinct biphasic pattern consisting of squamous differentiation superficially with epidermal connection overlying deeper dermal and subcutaneous infiltrative malignant ductal elements with gland formation should lead to consideration of this diagnosis. A thorough inspection for PNI also should be performed, as this finding was present in all of 5 cases and in 34% of reported cases in our literature review.

The differential diagnosis for SEDC includes SCC, metastatic adenocarcinoma with squamoid features, and eccrine tumors, including eccrine poroma, microcystic adnexal carcinoma (MAC), and porocarcinoma with squamous differentiation. The combination of histologic features with the immunoexpression profile of carcinoembryonic antigen (CEA), epithelial membrane antigen (EMA), cytokeratin (CK) 5/6, and p63 can effectively exclude the other entities in the differential and confirm the diagnosis of SEDC.^1,3,4 While the diagnosis of SEDC relies on the specific histologic features of multiple surface attachments and superficial squamoid changes with deep ductular elements, immunohistochemistry can nonetheless be adjunctive in difficult cases. Positive immunohistochemical staining for CEA and EMA can help to highlight and delineate true glandular elements, whereas CK5/6 highlights the overall contour of the tumor, displaying more clearly the multiple epidermal attachments and the subtle infiltrative nature of the deeper components of invasive cords and ducts. In addition, the combination of CK5/6 and p63 positivity supports the primary cutaneous nature of the lesion rather than metastatic adenocarcinoma.^13,20 Other markers of eccrine secretory coils, such as CK7, CAM5.2, and S100, also are sometimes used for confirmation, some of which can aid in distinction from noneccrine sweat gland differentiation, as CK7 and CAM5.2 are negative in both luminal and basal cells of the dermal duct while being positive within the secretory coil, and S100 protein is expressed within eccrine secretory coil but negative within the apocrine sweat glands.^2,4,21

The clinical findings from our chart review corroborated those reported in the literature. The mean age of SEDC in the 5 patients we reviewed was 81 years, and all cases presented on the head, consistent with the findings observed in the literature. Although 4 of our cases were male, there may not be a difference in risk based on sex as previously thought.¹ Our literature review revealed an almost equivalent percentage of male and female cases, with 52% being male.

Immunosuppression has been associated with an increased risk for SEDC. Our literature review revealed that approximately 9% (5/56) of cases occurred in immunosuppressed individuals. Two of these reported cases were in the setting of underlying chronic lymphocytic leukemia, 2 in individuals with a history of organ transplant, and 1 treated with azathioprine for myasthenia gravis.^2,4,10,12,13 Our chart review supported this correlation, as all 5 patients had a medical history potentially consistent with being in an immunocompromised state (Table). Notably, patient 5 represents a unique case of SEDC occurring in the setting of HIV. The patient had HIV for 33 years, with his most recent CD4⁺ count of 794 mm³ and HIV-1 RNA load of 35 copies/mL. Given that HIV-positive individuals may have more than a 2-fold increased risk of SCC, a greater degree of suspicion for SEDC should be maintained for these patients.^22,23

The etiology of SEDC is controversial but is thought to be either an SCC arising from eccrine glands or a variant of eccrine carcinoma with extensive squamoid differentiation.^{4,6,13,14,17,24} While SEDC certainly appears to share the proclivity for PNI with the malignant eccrine tumor MAC, it is simultaneously quite distinct, demonstrating nuclear pleomorphism and mitotic activity, both of which are lacking in the bland nature of MACs.^12,25

The exact prevalence of SEDC is difficult to ascertain because of its frequent misdiagnosis and variable nomenclature used within the literature. Most reported cases of SEDC are mistakenly diagnosed as SCC on the initial shave or punch biopsy because of superficial sampling. This also was the case in 4 of the patients we reviewed. In addition, there are reported cases of SEDC that were referred to by the investigators as cutaneous adenosquamous carcinoma (cASC), among other descriptors, such as ductal eccrine carcinoma with squamous differentiation, adnexal carcinoma with squamous and ductal differentiation, and syringoid eccrine carcinoma.^26-32 While the World Health Organization classifies SEDC as a distinct variant of cASC, which is a rare variant of SCC in itself, the 2 can be differentiated. Despite the similar clinical and histologic features shared between cASC and SEDC, the neoplastic aggregates in SEDC exhibit ductal differentiation containing lumina positive for CEA and EMA.⁴ Overall, we favor the term squamoid eccrine ductal carcinoma, as there has recently been more uniformity for the designation of this disease entity as such.

It is unclear whether the high incidence of local recurrence (23% [13/56]) of SEDC reported in the literature is related to the treatment modality employed (ie, wide local excision) or due to the innate aggressiveness of SEDC.^1,3,5 The literature has shown that MMS has lower recurrence rates than other treatments at 5-year follow-up for SCC (3.1%–5%) and eccrine carcinomas (0%–5%).^33,34 Although studies assessing tumor behavior or comparing treatment modalities are limited because of the rarity and underrecognition of SEDC, MMS has been used several times for SEDC with only 1 recurrence reported.^4,13,17,24 Given that all 5 of the patients we reviewed required more than 1 Mohs stage for complete tumor clearance and none demonstrated evidence of recurrence or metastasis (Table), we recommend MMS as the treatment of choice for SEDC.

Conclusion

Squamoid eccrine ductal carcinoma is a rare but likely underdiagnosed cutaneous tumor of uncertain etiology. Because of its propensity for recurrence and metastasis, excision of SEDC with complete circumferential peripheral and deep margin assessment with close follow-up is recommended.

Squamoid eccrine ductal carcinoma (SEDC) is an aggressive underrecognized cutaneous malignancy of unknown etiology.¹ It is most likely to occur in sun-exposed areas of the body, most commonly the head and neck. Risk factors include male sex, increased age, and chronic immunosuppression.^1-4 Current reports suggest that SEDC is likely a high-grade subtype of squamous cell carcinoma (SCC) with a high risk for local recurrence (25%) and metastasis (13%).^1,3,5,6 There are as few as 56 cases of SEDC reported in the literature; however, the number of cases may be closer to 100 due to SEDC being classified as either adenosquamous carcinoma of the skin or ductal eccrine carcinoma with squamous differentiation.¹

Clinically, SEDC mimics keratinocyte carcinomas. Histologically, SEDC is biphasic, with a superficial portion resembling well-differentiated SCC and a deeply invasive portion having infiltrative irregular cords with ductal differentiation. Perineural invasion (PNI) frequently is present. Multiple connections to the overlying epidermis also can be seen, serving as a subtle clue to the diagnosis on broad superficial specimens.^1-3 Due to superficial sampling, approximately 50% of reported cases are misdiagnosed as SCC during the initial biopsy.⁴ The diagnosis of SEDC often is made during complete excision when deeper tissue is sampled. Establishing an accurate diagnosis is important given the more aggressive nature of SEDC compared with SCC and its proclivity for PNI.^1,3,6 The purpose of this review is to increase awareness of this underrecognized entity and describe the histologic findings that help distinguish SEDC from SCC.

Patient Chart Review

We reviewed chart notes as well as frozen and formalin-fixed paraffin-embedded tissue sections from all 5 patients diagnosed with SEDC at a single institution between November 2018 and May 2020. The mean age of patients was 81 years, and 4 were male. Four of the patients presented for MMS with a preoperative diagnosis of SCC per the original biopsy results. Only 1 patient had a preoperative diagnosis of SEDC. The details of each case are recorded in the Table. All tumors were greater than 2 cm in diameter on initial presentation, were located on the head, and clinically resembled keratinocyte carcinoma with either a nodular or plaquelike appearance (Figure 1).

Intraoperative histologic examination of the excised tissue revealed a biphasic pattern consisting of superficial SCC features overlying deeper dermal and subcutaneous infiltrative malignant ductal elements with gland formation in all 5 patients (Figures 2–4). Immunohistochemical staining with cytokeratin AE1/AE3 revealed thin strands of carcinoma in the mid to deeper dermis with squamous differentiation and eccrine ductal differentiation (Figure 5), thus confirming the diagnosis in all 5 patients.

Literature Review

A PubMed review of the literature using the search term squamoid eccrine ductal carcinoma resulted in 28 articles, 19 of which were included in the review based on inclusion criteria (original articles available in English, in full text, and pertained to SEDC). Our review yielded 56 cases of SEDC.^1-19 The mean age of patients with SEDC was 72 years. The number of male and female cases was 52% (29/56) and 48% (27/56), respectively. The most common location of SEDC was on the head or neck (71% [40/56]), followed by the extremities (19% [11/56]). Immunosuppression was noted in 9% (5/56) of cases. Wide local excision was the most commonly employed treatment modality (91% [51/56]), with MMS being used in 4 patients (7%). Adjuvant radiation was reported in 5% (3/56) of cases. Perineural invasion was reported in 34% (19/56) of cases. Recurrence was seen in 23% (13/56) of cases, with a mean time to recurrence of 10.4 months. Metastasis to regional lymph nodes was observed in 13% (7/56) of cases, with 7% (4/56) of those cases having distant metastases.

Comment

Squamoid eccrine ductal carcinoma was successfully treated with MMS in all 5 of the patients we reviewed. Recognition of a distinct biphasic pattern consisting of squamous differentiation superficially with epidermal connection overlying deeper dermal and subcutaneous infiltrative malignant ductal elements with gland formation should lead to consideration of this diagnosis. A thorough inspection for PNI also should be performed, as this finding was present in all of 5 cases and in 34% of reported cases in our literature review.

The differential diagnosis for SEDC includes SCC, metastatic adenocarcinoma with squamoid features, and eccrine tumors, including eccrine poroma, microcystic adnexal carcinoma (MAC), and porocarcinoma with squamous differentiation. The combination of histologic features with the immunoexpression profile of carcinoembryonic antigen (CEA), epithelial membrane antigen (EMA), cytokeratin (CK) 5/6, and p63 can effectively exclude the other entities in the differential and confirm the diagnosis of SEDC.^1,3,4 While the diagnosis of SEDC relies on the specific histologic features of multiple surface attachments and superficial squamoid changes with deep ductular elements, immunohistochemistry can nonetheless be adjunctive in difficult cases. Positive immunohistochemical staining for CEA and EMA can help to highlight and delineate true glandular elements, whereas CK5/6 highlights the overall contour of the tumor, displaying more clearly the multiple epidermal attachments and the subtle infiltrative nature of the deeper components of invasive cords and ducts. In addition, the combination of CK5/6 and p63 positivity supports the primary cutaneous nature of the lesion rather than metastatic adenocarcinoma.^13,20 Other markers of eccrine secretory coils, such as CK7, CAM5.2, and S100, also are sometimes used for confirmation, some of which can aid in distinction from noneccrine sweat gland differentiation, as CK7 and CAM5.2 are negative in both luminal and basal cells of the dermal duct while being positive within the secretory coil, and S100 protein is expressed within eccrine secretory coil but negative within the apocrine sweat glands.^2,4,21

The clinical findings from our chart review corroborated those reported in the literature. The mean age of SEDC in the 5 patients we reviewed was 81 years, and all cases presented on the head, consistent with the findings observed in the literature. Although 4 of our cases were male, there may not be a difference in risk based on sex as previously thought.¹ Our literature review revealed an almost equivalent percentage of male and female cases, with 52% being male.

Immunosuppression has been associated with an increased risk for SEDC. Our literature review revealed that approximately 9% (5/56) of cases occurred in immunosuppressed individuals. Two of these reported cases were in the setting of underlying chronic lymphocytic leukemia, 2 in individuals with a history of organ transplant, and 1 treated with azathioprine for myasthenia gravis.^2,4,10,12,13 Our chart review supported this correlation, as all 5 patients had a medical history potentially consistent with being in an immunocompromised state (Table). Notably, patient 5 represents a unique case of SEDC occurring in the setting of HIV. The patient had HIV for 33 years, with his most recent CD4⁺ count of 794 mm³ and HIV-1 RNA load of 35 copies/mL. Given that HIV-positive individuals may have more than a 2-fold increased risk of SCC, a greater degree of suspicion for SEDC should be maintained for these patients.^22,23

The etiology of SEDC is controversial but is thought to be either an SCC arising from eccrine glands or a variant of eccrine carcinoma with extensive squamoid differentiation.^{4,6,13,14,17,24} While SEDC certainly appears to share the proclivity for PNI with the malignant eccrine tumor MAC, it is simultaneously quite distinct, demonstrating nuclear pleomorphism and mitotic activity, both of which are lacking in the bland nature of MACs.^12,25

The exact prevalence of SEDC is difficult to ascertain because of its frequent misdiagnosis and variable nomenclature used within the literature. Most reported cases of SEDC are mistakenly diagnosed as SCC on the initial shave or punch biopsy because of superficial sampling. This also was the case in 4 of the patients we reviewed. In addition, there are reported cases of SEDC that were referred to by the investigators as cutaneous adenosquamous carcinoma (cASC), among other descriptors, such as ductal eccrine carcinoma with squamous differentiation, adnexal carcinoma with squamous and ductal differentiation, and syringoid eccrine carcinoma.^26-32 While the World Health Organization classifies SEDC as a distinct variant of cASC, which is a rare variant of SCC in itself, the 2 can be differentiated. Despite the similar clinical and histologic features shared between cASC and SEDC, the neoplastic aggregates in SEDC exhibit ductal differentiation containing lumina positive for CEA and EMA.⁴ Overall, we favor the term squamoid eccrine ductal carcinoma, as there has recently been more uniformity for the designation of this disease entity as such.

It is unclear whether the high incidence of local recurrence (23% [13/56]) of SEDC reported in the literature is related to the treatment modality employed (ie, wide local excision) or due to the innate aggressiveness of SEDC.^1,3,5 The literature has shown that MMS has lower recurrence rates than other treatments at 5-year follow-up for SCC (3.1%–5%) and eccrine carcinomas (0%–5%).^33,34 Although studies assessing tumor behavior or comparing treatment modalities are limited because of the rarity and underrecognition of SEDC, MMS has been used several times for SEDC with only 1 recurrence reported.^4,13,17,24 Given that all 5 of the patients we reviewed required more than 1 Mohs stage for complete tumor clearance and none demonstrated evidence of recurrence or metastasis (Table), we recommend MMS as the treatment of choice for SEDC.

Conclusion

Squamoid eccrine ductal carcinoma is a rare but likely underdiagnosed cutaneous tumor of uncertain etiology. Because of its propensity for recurrence and metastasis, excision of SEDC with complete circumferential peripheral and deep margin assessment with close follow-up is recommended.

Granuloma annulare (GA) is a benign, cutaneous, granulomatous disease of unclear etiology. Typically, GA presents in young adults as asymptomatic, annular, flesh-colored to pink papules and plaques, commonly on the upper and lower extremities. Histologically, GA is characterized by mucin deposition, palisading or an interstitial granulomatous pattern, and collagen and elastic fiber degeneration.¹

Granuloma annulare has been associated with various medications and medical conditions, including diabetes mellitus, hyperlipidemia, thyroid disease, and HIV.¹ More recently, immune-checkpoint inhibitors (ICIs) have been reported to trigger GA.² We report a case of nivolumab-induced GA in a 54-year-old woman.

Case Report

A 54-year-old woman presented with an itchy rash on the upper extremities, face, and chest of 4 months’ duration. The patient noted that the rash started on the hands and progressed to include the arms, face, and chest. She also reported associated mild tenderness. She had a history of stage IV non–small-cell lung carcinoma with metastases to the ribs and adrenal glands. She had been started on biweekly intravenous infusions of the ICI nivolumab by her oncologist approximately 1 year prior to the current presentation after failing a course of conventional chemotherapy. The most recent positron emission tomography–computed tomography scan 1 month prior to presentation showed a stable lung mass with radiologic disappearance of metastases, indicating a favorable response to nivolumab. The patient also had a history of hypothyroidism and depression, which were treated with oral levothyroxine 75 μg once daily and oral sertraline 50 mg once daily, respectively, both for longer than 5 years.

Physical examination revealed annular, erythematous, flat-topped papules, some with surmounting fine scale, coalescing into larger plaques along the dorsal surface of the hands and arms (Figure 1) as well as the forehead and chest. A biopsy of a papule on the dorsal aspect of the left hand revealed nodules of histiocytes admixed with Langerhans giant cells within the dermis; mucin was noted centrally within some nodules (Figure 2). Periodic acid–Schiff staining was negative for fungal elements compared to control. Polarization of the specimen was negative for foreign bodies. The biopsy findings therefore were consistent with a diagnosis of GA.

Comment

Discovery of specific immune checkpoints in tumor-induced immunosuppression revolutionized oncologic therapy. An example is the programmed cell-death protein 1 (PD-1) receptor that is expressed on activated immune cells, including T cells and macrophages.^3,4 Upon binding to the PD-1 ligand (PD-L1), T-cell proliferation is inhibited, resulting in downregulation of the immune response. As a result, tumor cells have evolved to overexpress PD-L1 to evade immunologic detection.³ Nivolumab, a fully human IgG4 antibody to PD-1, has emerged along with other ICIs as effective treatments for numerous cancers, including melanoma and non–small-cell lung cancer. By disrupting downregulation of T cells, ICIs improve immune-mediated antitumor activity.³

However, the resulting immunologic disturbance by ICIs has been reported to induce various cutaneous and systemic immune-mediated adverse reactions, including granulomatous reactions such as sarcoidosis, GA, and a cutaneous sarcoidlike granulomatous reaction.^1,2,5,6 Our patient represents a rare case of nivolumab-induced GA.

Recent evidence suggests that GA might be caused in part by a cell-mediated hypersensitivity reaction that is regulated by a helper T cell subset 1 inflammatory reaction. Through release of cytokines by activated CD4⁺ T cells, macrophages are recruited, forming the granulomatous pattern and secreting enzymes that can degrade connective tissue. Nivolumab and other ICIs can thus trigger this reaction because their blockade of PD-1 enhances T cell–mediated immune reactions.² In addition, because macrophages themselves also express PD-1, ICIs can directly enhance macrophage recruitment and proliferation, further increasing the risk of a granulomatous reaction.⁴

Interestingly, cutaneous adverse reactions to nivolumab have been associated with improved survival in melanoma patients.⁷ The nature of this association with granulomatous reactions in general and with GA specifically remains to be determined.

Conclusion

Since the approval of the first PD-1 inhibitors, pembrolizumab and nivolumab, in 2014, other ICIs targeting the immune checkpoint pathway have been developed. Newer agents targeting PD-L1 (avelumab, atezolizumab, and durvalumab) were recently approved. Additionally, cemiplimab, another PD-1 inhibitor, was approved by the US Food and Drug Administration in 2018 for the treatment of advanced cutaneous squamous cell carcinoma.⁸ Indications for all ICIs also have expanded considerably.³ Therefore, the incidence of immune-mediated adverse reactions, including GA, is bound to increase. Physicians should be cognizant of this association to accurately diagnose and effectively treat adverse reactions in patients who are taking ICIs.

Granuloma annulare (GA) is a benign, cutaneous, granulomatous disease of unclear etiology. Typically, GA presents in young adults as asymptomatic, annular, flesh-colored to pink papules and plaques, commonly on the upper and lower extremities. Histologically, GA is characterized by mucin deposition, palisading or an interstitial granulomatous pattern, and collagen and elastic fiber degeneration.¹

Granuloma annulare has been associated with various medications and medical conditions, including diabetes mellitus, hyperlipidemia, thyroid disease, and HIV.¹ More recently, immune-checkpoint inhibitors (ICIs) have been reported to trigger GA.² We report a case of nivolumab-induced GA in a 54-year-old woman.

Case Report

A 54-year-old woman presented with an itchy rash on the upper extremities, face, and chest of 4 months’ duration. The patient noted that the rash started on the hands and progressed to include the arms, face, and chest. She also reported associated mild tenderness. She had a history of stage IV non–small-cell lung carcinoma with metastases to the ribs and adrenal glands. She had been started on biweekly intravenous infusions of the ICI nivolumab by her oncologist approximately 1 year prior to the current presentation after failing a course of conventional chemotherapy. The most recent positron emission tomography–computed tomography scan 1 month prior to presentation showed a stable lung mass with radiologic disappearance of metastases, indicating a favorable response to nivolumab. The patient also had a history of hypothyroidism and depression, which were treated with oral levothyroxine 75 μg once daily and oral sertraline 50 mg once daily, respectively, both for longer than 5 years.

Physical examination revealed annular, erythematous, flat-topped papules, some with surmounting fine scale, coalescing into larger plaques along the dorsal surface of the hands and arms (Figure 1) as well as the forehead and chest. A biopsy of a papule on the dorsal aspect of the left hand revealed nodules of histiocytes admixed with Langerhans giant cells within the dermis; mucin was noted centrally within some nodules (Figure 2). Periodic acid–Schiff staining was negative for fungal elements compared to control. Polarization of the specimen was negative for foreign bodies. The biopsy findings therefore were consistent with a diagnosis of GA.

Comment

Discovery of specific immune checkpoints in tumor-induced immunosuppression revolutionized oncologic therapy. An example is the programmed cell-death protein 1 (PD-1) receptor that is expressed on activated immune cells, including T cells and macrophages.^3,4 Upon binding to the PD-1 ligand (PD-L1), T-cell proliferation is inhibited, resulting in downregulation of the immune response. As a result, tumor cells have evolved to overexpress PD-L1 to evade immunologic detection.³ Nivolumab, a fully human IgG4 antibody to PD-1, has emerged along with other ICIs as effective treatments for numerous cancers, including melanoma and non–small-cell lung cancer. By disrupting downregulation of T cells, ICIs improve immune-mediated antitumor activity.³

However, the resulting immunologic disturbance by ICIs has been reported to induce various cutaneous and systemic immune-mediated adverse reactions, including granulomatous reactions such as sarcoidosis, GA, and a cutaneous sarcoidlike granulomatous reaction.^1,2,5,6 Our patient represents a rare case of nivolumab-induced GA.

Recent evidence suggests that GA might be caused in part by a cell-mediated hypersensitivity reaction that is regulated by a helper T cell subset 1 inflammatory reaction. Through release of cytokines by activated CD4⁺ T cells, macrophages are recruited, forming the granulomatous pattern and secreting enzymes that can degrade connective tissue. Nivolumab and other ICIs can thus trigger this reaction because their blockade of PD-1 enhances T cell–mediated immune reactions.² In addition, because macrophages themselves also express PD-1, ICIs can directly enhance macrophage recruitment and proliferation, further increasing the risk of a granulomatous reaction.⁴

Interestingly, cutaneous adverse reactions to nivolumab have been associated with improved survival in melanoma patients.⁷ The nature of this association with granulomatous reactions in general and with GA specifically remains to be determined.

Conclusion

Since the approval of the first PD-1 inhibitors, pembrolizumab and nivolumab, in 2014, other ICIs targeting the immune checkpoint pathway have been developed. Newer agents targeting PD-L1 (avelumab, atezolizumab, and durvalumab) were recently approved. Additionally, cemiplimab, another PD-1 inhibitor, was approved by the US Food and Drug Administration in 2018 for the treatment of advanced cutaneous squamous cell carcinoma.⁸ Indications for all ICIs also have expanded considerably.³ Therefore, the incidence of immune-mediated adverse reactions, including GA, is bound to increase. Physicians should be cognizant of this association to accurately diagnose and effectively treat adverse reactions in patients who are taking ICIs.

Granuloma annulare (GA) is a benign, cutaneous, granulomatous disease of unclear etiology. Typically, GA presents in young adults as asymptomatic, annular, flesh-colored to pink papules and plaques, commonly on the upper and lower extremities. Histologically, GA is characterized by mucin deposition, palisading or an interstitial granulomatous pattern, and collagen and elastic fiber degeneration.¹

Granuloma annulare has been associated with various medications and medical conditions, including diabetes mellitus, hyperlipidemia, thyroid disease, and HIV.¹ More recently, immune-checkpoint inhibitors (ICIs) have been reported to trigger GA.² We report a case of nivolumab-induced GA in a 54-year-old woman.

Case Report

A 54-year-old woman presented with an itchy rash on the upper extremities, face, and chest of 4 months’ duration. The patient noted that the rash started on the hands and progressed to include the arms, face, and chest. She also reported associated mild tenderness. She had a history of stage IV non–small-cell lung carcinoma with metastases to the ribs and adrenal glands. She had been started on biweekly intravenous infusions of the ICI nivolumab by her oncologist approximately 1 year prior to the current presentation after failing a course of conventional chemotherapy. The most recent positron emission tomography–computed tomography scan 1 month prior to presentation showed a stable lung mass with radiologic disappearance of metastases, indicating a favorable response to nivolumab. The patient also had a history of hypothyroidism and depression, which were treated with oral levothyroxine 75 μg once daily and oral sertraline 50 mg once daily, respectively, both for longer than 5 years.

Physical examination revealed annular, erythematous, flat-topped papules, some with surmounting fine scale, coalescing into larger plaques along the dorsal surface of the hands and arms (Figure 1) as well as the forehead and chest. A biopsy of a papule on the dorsal aspect of the left hand revealed nodules of histiocytes admixed with Langerhans giant cells within the dermis; mucin was noted centrally within some nodules (Figure 2). Periodic acid–Schiff staining was negative for fungal elements compared to control. Polarization of the specimen was negative for foreign bodies. The biopsy findings therefore were consistent with a diagnosis of GA.

Comment

Discovery of specific immune checkpoints in tumor-induced immunosuppression revolutionized oncologic therapy. An example is the programmed cell-death protein 1 (PD-1) receptor that is expressed on activated immune cells, including T cells and macrophages.^3,4 Upon binding to the PD-1 ligand (PD-L1), T-cell proliferation is inhibited, resulting in downregulation of the immune response. As a result, tumor cells have evolved to overexpress PD-L1 to evade immunologic detection.³ Nivolumab, a fully human IgG4 antibody to PD-1, has emerged along with other ICIs as effective treatments for numerous cancers, including melanoma and non–small-cell lung cancer. By disrupting downregulation of T cells, ICIs improve immune-mediated antitumor activity.³

However, the resulting immunologic disturbance by ICIs has been reported to induce various cutaneous and systemic immune-mediated adverse reactions, including granulomatous reactions such as sarcoidosis, GA, and a cutaneous sarcoidlike granulomatous reaction.^1,2,5,6 Our patient represents a rare case of nivolumab-induced GA.

Recent evidence suggests that GA might be caused in part by a cell-mediated hypersensitivity reaction that is regulated by a helper T cell subset 1 inflammatory reaction. Through release of cytokines by activated CD4⁺ T cells, macrophages are recruited, forming the granulomatous pattern and secreting enzymes that can degrade connective tissue. Nivolumab and other ICIs can thus trigger this reaction because their blockade of PD-1 enhances T cell–mediated immune reactions.² In addition, because macrophages themselves also express PD-1, ICIs can directly enhance macrophage recruitment and proliferation, further increasing the risk of a granulomatous reaction.⁴

Interestingly, cutaneous adverse reactions to nivolumab have been associated with improved survival in melanoma patients.⁷ The nature of this association with granulomatous reactions in general and with GA specifically remains to be determined.

Conclusion

Since the approval of the first PD-1 inhibitors, pembrolizumab and nivolumab, in 2014, other ICIs targeting the immune checkpoint pathway have been developed. Newer agents targeting PD-L1 (avelumab, atezolizumab, and durvalumab) were recently approved. Additionally, cemiplimab, another PD-1 inhibitor, was approved by the US Food and Drug Administration in 2018 for the treatment of advanced cutaneous squamous cell carcinoma.⁸ Indications for all ICIs also have expanded considerably.³ Therefore, the incidence of immune-mediated adverse reactions, including GA, is bound to increase. Physicians should be cognizant of this association to accurately diagnose and effectively treat adverse reactions in patients who are taking ICIs.

In the first clinical trial of a topical histone deacetylase (HDAC) inhibitor, remetinostat showed clinical efficacy across several basal cell carcinoma (BCC) tumor types, according to research presented at the annual meeting of the Society for Investigative Dermatology.

“Our results demonstrate a clinically significant decrease in tumor size in response to 6 weeks of topical 1% remetinostat therapy in 70% of per-protocol tumors, with 55% reaching complete pathological resolution,” James M. Kilgour, MD, a postdoctoral research fellow at the Sarin Lab at Stanford (Calif.) University, said at the meeting.

Surgical excision is the preferred treatment for BCC, but there is still a need for noninvasive treatment options, Dr. Kilgour said. “Given the potential morbidity associated with excision, particularly for patients experiencing multiple or recurrent tumors, such as the immunosuppressed or patients with Gorlin syndrome, an effective and tolerable topical therapy would be a significant benefit,” he noted.

Previously, in an in silico screen experiment, Dr. Kilgour and colleagues identified HDAC inhibitors as a “top predicted therapeutic” for BCC treatment, and found that in mice studies, HDAC inhibitors were able to suppress the growth of BCC cell lines and BCC allografts.

Remetinostat, a pan-HDAC inhibitor, is being investigated as a treatment for cutaneous T-cell lymphoma.

HDAC inhibitors are thought to “alter expression of key oncogenes and tumor suppressors through epigenetic modification of histone and nonhistone proteins,” he noted.

To evaluate the efficacy of topical remetinostat for BCC, the investigators enrolled 30 patients with 49 BCC tumors in a phase 2, open-label, single-arm trial. Participants had tumors that were greater than 5 mm in diameter and had been referred to surgery at Stanford before enrollment. Patients were a mean of 59 years old, 63% were men, and 90% were White; 59.2% of participants had tumors with a diameter greater than 10 mm, the rest had tumors with a diameter of 10 mm or less.

After the tumors were photographed and measured, participants received 6 weeks of topical remetinostat therapy, followed by final measurement and photography of the tumors at 8 weeks and surgical excision. Topical remetinostat 1% gel was applied three times per day under bandage occlusion.

Overall, 25 participants with 33 tumors were included in the per-protocol analysis. At 8 weeks, there was at least a 30% decrease in diameter from baseline for 69.7% of tumors in these patients, with 17 of 33 tumors showing a complete response by week 8.

Regarding tumor subtypes, there was a 100% overall response rate for the 6 superficial BCC tumors (1 partial response, 5 complete responses), a 68.2% ORR for the 22 nodular tumors (5 partial responses, 10 complete responses), and a 66.7% ORR for the 3 infiltrative tumors (no partial responses, 2 complete responses). There were no partial or complete responses for the two micronodular tumors.

Most adverse events in the study were localized drug reactions, with no serious or systemic adverse events, Dr. Kilgour noted, with 10 tumors demonstrating either no reaction or a grade 1 reaction, and 23 tumors having a grade 2 or grade 3 response.

The investigators also used imaging (ImageJ) software to evaluate the average decrease in cross-sectional tumor area. The results of the analysis showed an average decrease at 8 weeks from baseline of 71.5%. In addition, histological assessment at 8 weeks demonstrated that 54.8% of tumors had complete pathological resolution.

“In the future, we advocate for a follow-up blinded, randomized, controlled trial of remetinostat with greater participant diversity,” Dr. Kilgour said. “Specifically, greater power is needed to understand which histological subtypes of BCC will respond best to the treatment and we need to understand the long-term durability of tumor resolution.”

 

Remetinostat promising as topical BCC therapy

In an interview, Beth G. Goldstein, MD, a dermatologist and Mohs surgeon in Chapel Hill, N.C., noted that the preliminary study was “an exciting report of a safe, well-tolerated nonsurgical option for patients with superficial BCCs on the trunk and extremities,” which has potential to be used in the future for nonsuperficial BCCs. The study shows that superficial BCCs can respond at a rate of 100% on nonfacial areas, said Dr. Goldstein, who was not involved in the research. “These lesions can be quite large with higher chances of recurrence and difficulty with wound care.

“This type of directed therapy hopefully continues to be perfected for treatment of BCC that avoids scarring and is well tolerated,” she added.

Dr. Goldstein commented that complete pathological resolution of 54.8% “was still unacceptably low for the remaining tumor types.” For those cases, she said remetinostat could possibly “provide a topical option as an adjunctive treatment for potentially reducing the size of the BCC prior to surgical removal,” as an alternative to a systemic therapy like vismodegib (Erivedge).

Dr. Goldstein said the strengths of the study were in the variety of tumors, close follow-up with histologic evaluation and safety signals. In terms of limitations, she said whether there were any cases of Gorlin syndrome was not clear. In addition, at least 30% of BCCs have a mixed tumor type on Mohs surgery that differs from the original biopsy, and “there was no mention if the residual tumor remained with the same histology,” she said.

In the future, a large, randomized trial is warranted to stratify for Gorlin syndrome, patients who are immunosuppressed, and additional tumor types that were underrepresented in this study, such as micronodular tumors, Dr. Goldstein said. Future studies also should examine how remetinostat impacts BCC in facial areas, the effect of multiple applications, and how the therapy performs as an adjunctive treatment before surgery.

This study was funded by Medivir, the Damon Runyon Foundation, National Cancer Institute, an American Skin Association Hambrick Medical Student grant, and Stanford Medical Scholars. Dr. Kilgour and Dr. Goldstein reported no relevant financial disclosures.

In the first clinical trial of a topical histone deacetylase (HDAC) inhibitor, remetinostat showed clinical efficacy across several basal cell carcinoma (BCC) tumor types, according to research presented at the annual meeting of the Society for Investigative Dermatology.

“Our results demonstrate a clinically significant decrease in tumor size in response to 6 weeks of topical 1% remetinostat therapy in 70% of per-protocol tumors, with 55% reaching complete pathological resolution,” James M. Kilgour, MD, a postdoctoral research fellow at the Sarin Lab at Stanford (Calif.) University, said at the meeting.

Surgical excision is the preferred treatment for BCC, but there is still a need for noninvasive treatment options, Dr. Kilgour said. “Given the potential morbidity associated with excision, particularly for patients experiencing multiple or recurrent tumors, such as the immunosuppressed or patients with Gorlin syndrome, an effective and tolerable topical therapy would be a significant benefit,” he noted.

Previously, in an in silico screen experiment, Dr. Kilgour and colleagues identified HDAC inhibitors as a “top predicted therapeutic” for BCC treatment, and found that in mice studies, HDAC inhibitors were able to suppress the growth of BCC cell lines and BCC allografts.

Remetinostat, a pan-HDAC inhibitor, is being investigated as a treatment for cutaneous T-cell lymphoma.

HDAC inhibitors are thought to “alter expression of key oncogenes and tumor suppressors through epigenetic modification of histone and nonhistone proteins,” he noted.

To evaluate the efficacy of topical remetinostat for BCC, the investigators enrolled 30 patients with 49 BCC tumors in a phase 2, open-label, single-arm trial. Participants had tumors that were greater than 5 mm in diameter and had been referred to surgery at Stanford before enrollment. Patients were a mean of 59 years old, 63% were men, and 90% were White; 59.2% of participants had tumors with a diameter greater than 10 mm, the rest had tumors with a diameter of 10 mm or less.

After the tumors were photographed and measured, participants received 6 weeks of topical remetinostat therapy, followed by final measurement and photography of the tumors at 8 weeks and surgical excision. Topical remetinostat 1% gel was applied three times per day under bandage occlusion.

Overall, 25 participants with 33 tumors were included in the per-protocol analysis. At 8 weeks, there was at least a 30% decrease in diameter from baseline for 69.7% of tumors in these patients, with 17 of 33 tumors showing a complete response by week 8.

Regarding tumor subtypes, there was a 100% overall response rate for the 6 superficial BCC tumors (1 partial response, 5 complete responses), a 68.2% ORR for the 22 nodular tumors (5 partial responses, 10 complete responses), and a 66.7% ORR for the 3 infiltrative tumors (no partial responses, 2 complete responses). There were no partial or complete responses for the two micronodular tumors.

Most adverse events in the study were localized drug reactions, with no serious or systemic adverse events, Dr. Kilgour noted, with 10 tumors demonstrating either no reaction or a grade 1 reaction, and 23 tumors having a grade 2 or grade 3 response.

The investigators also used imaging (ImageJ) software to evaluate the average decrease in cross-sectional tumor area. The results of the analysis showed an average decrease at 8 weeks from baseline of 71.5%. In addition, histological assessment at 8 weeks demonstrated that 54.8% of tumors had complete pathological resolution.

“In the future, we advocate for a follow-up blinded, randomized, controlled trial of remetinostat with greater participant diversity,” Dr. Kilgour said. “Specifically, greater power is needed to understand which histological subtypes of BCC will respond best to the treatment and we need to understand the long-term durability of tumor resolution.”

 

Remetinostat promising as topical BCC therapy

In an interview, Beth G. Goldstein, MD, a dermatologist and Mohs surgeon in Chapel Hill, N.C., noted that the preliminary study was “an exciting report of a safe, well-tolerated nonsurgical option for patients with superficial BCCs on the trunk and extremities,” which has potential to be used in the future for nonsuperficial BCCs. The study shows that superficial BCCs can respond at a rate of 100% on nonfacial areas, said Dr. Goldstein, who was not involved in the research. “These lesions can be quite large with higher chances of recurrence and difficulty with wound care.

“This type of directed therapy hopefully continues to be perfected for treatment of BCC that avoids scarring and is well tolerated,” she added.

Dr. Goldstein commented that complete pathological resolution of 54.8% “was still unacceptably low for the remaining tumor types.” For those cases, she said remetinostat could possibly “provide a topical option as an adjunctive treatment for potentially reducing the size of the BCC prior to surgical removal,” as an alternative to a systemic therapy like vismodegib (Erivedge).

Dr. Goldstein said the strengths of the study were in the variety of tumors, close follow-up with histologic evaluation and safety signals. In terms of limitations, she said whether there were any cases of Gorlin syndrome was not clear. In addition, at least 30% of BCCs have a mixed tumor type on Mohs surgery that differs from the original biopsy, and “there was no mention if the residual tumor remained with the same histology,” she said.

In the future, a large, randomized trial is warranted to stratify for Gorlin syndrome, patients who are immunosuppressed, and additional tumor types that were underrepresented in this study, such as micronodular tumors, Dr. Goldstein said. Future studies also should examine how remetinostat impacts BCC in facial areas, the effect of multiple applications, and how the therapy performs as an adjunctive treatment before surgery.

This study was funded by Medivir, the Damon Runyon Foundation, National Cancer Institute, an American Skin Association Hambrick Medical Student grant, and Stanford Medical Scholars. Dr. Kilgour and Dr. Goldstein reported no relevant financial disclosures.

In the first clinical trial of a topical histone deacetylase (HDAC) inhibitor, remetinostat showed clinical efficacy across several basal cell carcinoma (BCC) tumor types, according to research presented at the annual meeting of the Society for Investigative Dermatology.

“Our results demonstrate a clinically significant decrease in tumor size in response to 6 weeks of topical 1% remetinostat therapy in 70% of per-protocol tumors, with 55% reaching complete pathological resolution,” James M. Kilgour, MD, a postdoctoral research fellow at the Sarin Lab at Stanford (Calif.) University, said at the meeting.

Surgical excision is the preferred treatment for BCC, but there is still a need for noninvasive treatment options, Dr. Kilgour said. “Given the potential morbidity associated with excision, particularly for patients experiencing multiple or recurrent tumors, such as the immunosuppressed or patients with Gorlin syndrome, an effective and tolerable topical therapy would be a significant benefit,” he noted.

Previously, in an in silico screen experiment, Dr. Kilgour and colleagues identified HDAC inhibitors as a “top predicted therapeutic” for BCC treatment, and found that in mice studies, HDAC inhibitors were able to suppress the growth of BCC cell lines and BCC allografts.

Remetinostat, a pan-HDAC inhibitor, is being investigated as a treatment for cutaneous T-cell lymphoma.

HDAC inhibitors are thought to “alter expression of key oncogenes and tumor suppressors through epigenetic modification of histone and nonhistone proteins,” he noted.

To evaluate the efficacy of topical remetinostat for BCC, the investigators enrolled 30 patients with 49 BCC tumors in a phase 2, open-label, single-arm trial. Participants had tumors that were greater than 5 mm in diameter and had been referred to surgery at Stanford before enrollment. Patients were a mean of 59 years old, 63% were men, and 90% were White; 59.2% of participants had tumors with a diameter greater than 10 mm, the rest had tumors with a diameter of 10 mm or less.

After the tumors were photographed and measured, participants received 6 weeks of topical remetinostat therapy, followed by final measurement and photography of the tumors at 8 weeks and surgical excision. Topical remetinostat 1% gel was applied three times per day under bandage occlusion.

Overall, 25 participants with 33 tumors were included in the per-protocol analysis. At 8 weeks, there was at least a 30% decrease in diameter from baseline for 69.7% of tumors in these patients, with 17 of 33 tumors showing a complete response by week 8.

Regarding tumor subtypes, there was a 100% overall response rate for the 6 superficial BCC tumors (1 partial response, 5 complete responses), a 68.2% ORR for the 22 nodular tumors (5 partial responses, 10 complete responses), and a 66.7% ORR for the 3 infiltrative tumors (no partial responses, 2 complete responses). There were no partial or complete responses for the two micronodular tumors.

Most adverse events in the study were localized drug reactions, with no serious or systemic adverse events, Dr. Kilgour noted, with 10 tumors demonstrating either no reaction or a grade 1 reaction, and 23 tumors having a grade 2 or grade 3 response.

The investigators also used imaging (ImageJ) software to evaluate the average decrease in cross-sectional tumor area. The results of the analysis showed an average decrease at 8 weeks from baseline of 71.5%. In addition, histological assessment at 8 weeks demonstrated that 54.8% of tumors had complete pathological resolution.

“In the future, we advocate for a follow-up blinded, randomized, controlled trial of remetinostat with greater participant diversity,” Dr. Kilgour said. “Specifically, greater power is needed to understand which histological subtypes of BCC will respond best to the treatment and we need to understand the long-term durability of tumor resolution.”

 

Remetinostat promising as topical BCC therapy

In an interview, Beth G. Goldstein, MD, a dermatologist and Mohs surgeon in Chapel Hill, N.C., noted that the preliminary study was “an exciting report of a safe, well-tolerated nonsurgical option for patients with superficial BCCs on the trunk and extremities,” which has potential to be used in the future for nonsuperficial BCCs. The study shows that superficial BCCs can respond at a rate of 100% on nonfacial areas, said Dr. Goldstein, who was not involved in the research. “These lesions can be quite large with higher chances of recurrence and difficulty with wound care.

“This type of directed therapy hopefully continues to be perfected for treatment of BCC that avoids scarring and is well tolerated,” she added.

Dr. Goldstein commented that complete pathological resolution of 54.8% “was still unacceptably low for the remaining tumor types.” For those cases, she said remetinostat could possibly “provide a topical option as an adjunctive treatment for potentially reducing the size of the BCC prior to surgical removal,” as an alternative to a systemic therapy like vismodegib (Erivedge).

Dr. Goldstein said the strengths of the study were in the variety of tumors, close follow-up with histologic evaluation and safety signals. In terms of limitations, she said whether there were any cases of Gorlin syndrome was not clear. In addition, at least 30% of BCCs have a mixed tumor type on Mohs surgery that differs from the original biopsy, and “there was no mention if the residual tumor remained with the same histology,” she said.

In the future, a large, randomized trial is warranted to stratify for Gorlin syndrome, patients who are immunosuppressed, and additional tumor types that were underrepresented in this study, such as micronodular tumors, Dr. Goldstein said. Future studies also should examine how remetinostat impacts BCC in facial areas, the effect of multiple applications, and how the therapy performs as an adjunctive treatment before surgery.

This study was funded by Medivir, the Damon Runyon Foundation, National Cancer Institute, an American Skin Association Hambrick Medical Student grant, and Stanford Medical Scholars. Dr. Kilgour and Dr. Goldstein reported no relevant financial disclosures.

To the Editor:

In an interesting analysis, Brady and Hossler¹ (Cutis. 2020;106:315-317) highlighted the limitations of histopathologic biopsy margin evaluation for cutaneous basal cell carcinoma (BCC). Taking into consideration the high prevalence of BCC and its medical and economic impact on the health care system, the issue raised by the authors is an important one. They proposed that pathologists may omit reporting margins or clarify the limitations in their reports. It is a valid suggestion; however, in practice, margin evaluation is not always a simple process and is influenced by a number of factors.

The subject of optimum margins for BCC has been debated over decades now; however, ambiguity and lack of definitive guidelines on certain aspects still remain, leading to a lack of standardization and variability in reporting, which opens potential for error. In anatomical pathology, the biopsies for malignancies are interpreted to confirm diagnosis and perform risk assessment, with evaluation of margins generally reserved for subsequent definitive resections. Typically, margins are not required by clinicians or reported by pathologists in common endoscopic (eg, stomach, colon) or needle core (eg, prostate, breast) biopsies. Skin holds a rather unique position in which margin evaluation is not just limited to excisions. With the exception of samples generated from electrodesiccation and curettage, it is common practice by some laboratories to report margins on most specimens of cutaneous malignancies.

In simple terms, when margins are labeled negative there should be no residual disease, and when they are deemed positive there should be disease still persisting in the patient. Margin evaluation for BCC on biopsies falls short on both fronts. In one analysis, 24% (34/143) of shave biopsies reported with negative margins displayed residual BCC in ensuing re-excisions (negative predictive value: 76%).² Standard bread-loafing, en-face margins and inking for orientation utilized to provide a thorough margin evaluation of excisions cannot be optimally achieved on small skin biopsies. Microscopic sections for analysis are 2-dimensional representations of 3-dimensional structures. Slides prepared can miss deeply embedded outermost margins, positioned parallel to the plane of sectioning, thereby creating blind spots where margins cannot be precisely assessed and generating an inherent limitation in evaluation. Exhaustive deeper levels done routinely can address this issue to a certain degree; however, it can be an impractical solution with cost implications and delay in turnaround time.

Conversely, it also is common to encounter absence of residual BCC in re-excisions in which the original biopsy margins were labeled positive. In one analysis, 49% of BCC patients (n=100) with positive biopsy margins did not display residual neoplasm on following re-excisions.³ Localized biopsy site immune response as a cause of postbiopsy regression of residual tumor has been hypothesized to produce this phenomenon. Moreover, initial biopsies may eliminate the majority of the tumor with only minimal disease persisting. Re-excisions submitted in toto allow for a systematic examination; however, areas in between sections still remain where minute residual tumor may hide. Searching for such occult foci generally is not aggressively pursued via deeper levels unless the margins of re-excision are in question.

Superficial-type BCC (or superficial multifocal BCC) is a major factor in precluding precise biopsy margin evaluation. In a study where initial biopsies reported with negative margins displayed residual BCC in subsequent re-excisions, 91% (31/34) of residual BCCs were of superficial variety.² Clinically, superficial BCC frequently has indistinct borders with subtle subclinical peripheral progression. It has a tendency to expand radially, with the clinical appearance deceptively smaller than its true extent. In a plane of histopathologic section, superficial BCC may exhibit skip zones within the epidermis. Even though the margin may seem uninvolved on the slide, a noncontiguous focus may still emerge beyond the “negative” margin. Because superficial pattern is not unusual as one of the components of mixed histology (composite) BCC, this issue is not just limited to tumors specifically designated as superficial type.⁴

The intent of a procedure is important to recognize. If a biopsy is done with the intention of diagnosis only, the pathologic assessment can be limited to tumor identification and core data elements, with margin evaluation reserved for excisions done with therapeutic intent. However, the intent is not always clear, which adds to ambiguity on when to report margins. It is not uncommon to find saucerization shaves or large punch biopsies for BCC carried out with a therapeutic intent. The status of margin is desired in such samples; however, the intent is not always clearly communicated on requisitions. To avoid any gaps in communication, some pathologists may err on the side of caution and start routinely reporting margins on biopsies.

Taking into account the inaccuracy of margin assessment in biopsies, an argument for omitting margin reporting is plausible. Although dermatologists are the major contributors of skin samples, pathology laboratories cater to a broader clientele. Other physicians from different surgical and medical specialities also perform skin biopsies, and catering to a variety of specialities adds another layer of complexity. A dermatologist may appreciate the debate regarding reliability of margins; however, a physician from another speciality who is not as familiar with the diseases of the integument may lack proper understanding. Omitting margin reporting may lead to misinterpretations or false assumptions, such as, “The margins must be uninvolved, otherwise the pathologist would have said something.” This also can generate additional phone or email inquiries and second review requests. Rather than completely omitting them, another strategy can be to report margins in more quantitative terms. One reporting approach is to have 3 categories of involved, uninvolved, and uninvolved but close for margins less than 1 mm. The cases in the third category may require greater scrutiny by deeper levels or an added caveat in the comment addressing the limitation. If the status of margins is not reported due to a certain reason, a short comment can be added to explain the reason.

In sum, clinicians should recognize that “margin negative” on skin biopsy does not always equate to “completely excised.” Margin status on biopsies is a data item that essentially provides a probability of margin clearance. Completely omitting the margin status on all biopsies may not be the most prudent approach; however, improved guidelines and modifications to enhance the reporting are definitely required.

References

1. Brady MC, Hossler EW. Reliability of biopsy margin status for basal cell carcinoma: a retrospective study. Cutis. 2020;106:315-317.
    
2. Willardson HB, Lombardo J, Raines M, et al. Predictive value of basal cell carcinoma biopsies with negative margins: a retrospective cohort study. J Am Acad Dermatol. 2018;79:42-46.
    
3. Yuan Y, Duff ML, Sammons DL, et al. Retrospective chart review of skin cancer presence in the wide excisions. World J Clin Cases. 2014;2:52-56.
    
4. Cohen PR, Schulze KE, Nelson BR. Basal cell carcinoma with mixed histology: a possible pathogenesis for recurrent skin cancer. Dermatol Surg. 2006;32:542-551.

Continue to: Author's Response...

Authors’ Response

We appreciate the thorough and thoughtful comments in the Letter to the Editor. We agree with the author’s assertion that negative margins on skin specimens does not equate to “completely excised” and that the intent of the clinician is not always clear, even when the pathologist has ready access to the clinician’s notes, as was the case for the majority of specimens included in our study.

There is already variability in how pathologists report margins, including the specific verbiage used, at least for melanocytic lesions.¹ The choice of whether or not to report margins and the meaning of those margins is complex due to the uncertainty inherent in margin assessment. Quantifying this uncertainty was the main reason for our study. Ultimately, the pathologist’s decision on whether and how to report margins should be focused on improving patient outcomes. There are benefits and drawbacks to all approaches, and our goal is to provide more information for clinicians and pathologists so that they may better care for their patients. Understanding the limitations of margins on submitted skin specimens—whether margins are reported or not—can only serve to guide improve clinical decision-making. 

We also agree that the breadth of specialties of submitting clinicians make reporting of margins difficult, and there is likely similar breadth in their understanding of the nuances of margin assessment and reports. The solution to this problem is adequate education regarding the limitations of a pathology report, and specifically what is meant when margins are (or are not) reported on skin specimens. How to best educate the myriad clinicians who submit biopsies is, of course, the ultimate challenge.

We hope that our study adds information to this ongoing debate regarding margin status reporting, and we appreciate the discussion points raised by the author.

Eric Hossler, MD; Mary Brady, MD

From the Department of Dermatology, Geisinger Health System, Danville, Pennsylvania.

The authors report no conflict of interest.

Reference

1. Sellheyer K, Bergfeld WF, Stewart E, et al. Evaluation of surgical margins in melanocytic lesions: a survey among 152 dermatopathologists.J Cutan Pathol. 2005;32:293-299.

To the Editor:

In an interesting analysis, Brady and Hossler¹ (Cutis. 2020;106:315-317) highlighted the limitations of histopathologic biopsy margin evaluation for cutaneous basal cell carcinoma (BCC). Taking into consideration the high prevalence of BCC and its medical and economic impact on the health care system, the issue raised by the authors is an important one. They proposed that pathologists may omit reporting margins or clarify the limitations in their reports. It is a valid suggestion; however, in practice, margin evaluation is not always a simple process and is influenced by a number of factors.

The subject of optimum margins for BCC has been debated over decades now; however, ambiguity and lack of definitive guidelines on certain aspects still remain, leading to a lack of standardization and variability in reporting, which opens potential for error. In anatomical pathology, the biopsies for malignancies are interpreted to confirm diagnosis and perform risk assessment, with evaluation of margins generally reserved for subsequent definitive resections. Typically, margins are not required by clinicians or reported by pathologists in common endoscopic (eg, stomach, colon) or needle core (eg, prostate, breast) biopsies. Skin holds a rather unique position in which margin evaluation is not just limited to excisions. With the exception of samples generated from electrodesiccation and curettage, it is common practice by some laboratories to report margins on most specimens of cutaneous malignancies.

In simple terms, when margins are labeled negative there should be no residual disease, and when they are deemed positive there should be disease still persisting in the patient. Margin evaluation for BCC on biopsies falls short on both fronts. In one analysis, 24% (34/143) of shave biopsies reported with negative margins displayed residual BCC in ensuing re-excisions (negative predictive value: 76%).² Standard bread-loafing, en-face margins and inking for orientation utilized to provide a thorough margin evaluation of excisions cannot be optimally achieved on small skin biopsies. Microscopic sections for analysis are 2-dimensional representations of 3-dimensional structures. Slides prepared can miss deeply embedded outermost margins, positioned parallel to the plane of sectioning, thereby creating blind spots where margins cannot be precisely assessed and generating an inherent limitation in evaluation. Exhaustive deeper levels done routinely can address this issue to a certain degree; however, it can be an impractical solution with cost implications and delay in turnaround time.

Conversely, it also is common to encounter absence of residual BCC in re-excisions in which the original biopsy margins were labeled positive. In one analysis, 49% of BCC patients (n=100) with positive biopsy margins did not display residual neoplasm on following re-excisions.³ Localized biopsy site immune response as a cause of postbiopsy regression of residual tumor has been hypothesized to produce this phenomenon. Moreover, initial biopsies may eliminate the majority of the tumor with only minimal disease persisting. Re-excisions submitted in toto allow for a systematic examination; however, areas in between sections still remain where minute residual tumor may hide. Searching for such occult foci generally is not aggressively pursued via deeper levels unless the margins of re-excision are in question.

Superficial-type BCC (or superficial multifocal BCC) is a major factor in precluding precise biopsy margin evaluation. In a study where initial biopsies reported with negative margins displayed residual BCC in subsequent re-excisions, 91% (31/34) of residual BCCs were of superficial variety.² Clinically, superficial BCC frequently has indistinct borders with subtle subclinical peripheral progression. It has a tendency to expand radially, with the clinical appearance deceptively smaller than its true extent. In a plane of histopathologic section, superficial BCC may exhibit skip zones within the epidermis. Even though the margin may seem uninvolved on the slide, a noncontiguous focus may still emerge beyond the “negative” margin. Because superficial pattern is not unusual as one of the components of mixed histology (composite) BCC, this issue is not just limited to tumors specifically designated as superficial type.⁴

The intent of a procedure is important to recognize. If a biopsy is done with the intention of diagnosis only, the pathologic assessment can be limited to tumor identification and core data elements, with margin evaluation reserved for excisions done with therapeutic intent. However, the intent is not always clear, which adds to ambiguity on when to report margins. It is not uncommon to find saucerization shaves or large punch biopsies for BCC carried out with a therapeutic intent. The status of margin is desired in such samples; however, the intent is not always clearly communicated on requisitions. To avoid any gaps in communication, some pathologists may err on the side of caution and start routinely reporting margins on biopsies.

Taking into account the inaccuracy of margin assessment in biopsies, an argument for omitting margin reporting is plausible. Although dermatologists are the major contributors of skin samples, pathology laboratories cater to a broader clientele. Other physicians from different surgical and medical specialities also perform skin biopsies, and catering to a variety of specialities adds another layer of complexity. A dermatologist may appreciate the debate regarding reliability of margins; however, a physician from another speciality who is not as familiar with the diseases of the integument may lack proper understanding. Omitting margin reporting may lead to misinterpretations or false assumptions, such as, “The margins must be uninvolved, otherwise the pathologist would have said something.” This also can generate additional phone or email inquiries and second review requests. Rather than completely omitting them, another strategy can be to report margins in more quantitative terms. One reporting approach is to have 3 categories of involved, uninvolved, and uninvolved but close for margins less than 1 mm. The cases in the third category may require greater scrutiny by deeper levels or an added caveat in the comment addressing the limitation. If the status of margins is not reported due to a certain reason, a short comment can be added to explain the reason.

In sum, clinicians should recognize that “margin negative” on skin biopsy does not always equate to “completely excised.” Margin status on biopsies is a data item that essentially provides a probability of margin clearance. Completely omitting the margin status on all biopsies may not be the most prudent approach; however, improved guidelines and modifications to enhance the reporting are definitely required.

References

1. Brady MC, Hossler EW. Reliability of biopsy margin status for basal cell carcinoma: a retrospective study. Cutis. 2020;106:315-317.
    
2. Willardson HB, Lombardo J, Raines M, et al. Predictive value of basal cell carcinoma biopsies with negative margins: a retrospective cohort study. J Am Acad Dermatol. 2018;79:42-46.
    
3. Yuan Y, Duff ML, Sammons DL, et al. Retrospective chart review of skin cancer presence in the wide excisions. World J Clin Cases. 2014;2:52-56.
    
4. Cohen PR, Schulze KE, Nelson BR. Basal cell carcinoma with mixed histology: a possible pathogenesis for recurrent skin cancer. Dermatol Surg. 2006;32:542-551.

Continue to: Author's Response...

Authors’ Response

We appreciate the thorough and thoughtful comments in the Letter to the Editor. We agree with the author’s assertion that negative margins on skin specimens does not equate to “completely excised” and that the intent of the clinician is not always clear, even when the pathologist has ready access to the clinician’s notes, as was the case for the majority of specimens included in our study.

There is already variability in how pathologists report margins, including the specific verbiage used, at least for melanocytic lesions.¹ The choice of whether or not to report margins and the meaning of those margins is complex due to the uncertainty inherent in margin assessment. Quantifying this uncertainty was the main reason for our study. Ultimately, the pathologist’s decision on whether and how to report margins should be focused on improving patient outcomes. There are benefits and drawbacks to all approaches, and our goal is to provide more information for clinicians and pathologists so that they may better care for their patients. Understanding the limitations of margins on submitted skin specimens—whether margins are reported or not—can only serve to guide improve clinical decision-making. 

We also agree that the breadth of specialties of submitting clinicians make reporting of margins difficult, and there is likely similar breadth in their understanding of the nuances of margin assessment and reports. The solution to this problem is adequate education regarding the limitations of a pathology report, and specifically what is meant when margins are (or are not) reported on skin specimens. How to best educate the myriad clinicians who submit biopsies is, of course, the ultimate challenge.

We hope that our study adds information to this ongoing debate regarding margin status reporting, and we appreciate the discussion points raised by the author.

Eric Hossler, MD; Mary Brady, MD

From the Department of Dermatology, Geisinger Health System, Danville, Pennsylvania.

The authors report no conflict of interest.

Reference

1. Sellheyer K, Bergfeld WF, Stewart E, et al. Evaluation of surgical margins in melanocytic lesions: a survey among 152 dermatopathologists.J Cutan Pathol. 2005;32:293-299.

To the Editor:

In an interesting analysis, Brady and Hossler¹ (Cutis. 2020;106:315-317) highlighted the limitations of histopathologic biopsy margin evaluation for cutaneous basal cell carcinoma (BCC). Taking into consideration the high prevalence of BCC and its medical and economic impact on the health care system, the issue raised by the authors is an important one. They proposed that pathologists may omit reporting margins or clarify the limitations in their reports. It is a valid suggestion; however, in practice, margin evaluation is not always a simple process and is influenced by a number of factors.

The subject of optimum margins for BCC has been debated over decades now; however, ambiguity and lack of definitive guidelines on certain aspects still remain, leading to a lack of standardization and variability in reporting, which opens potential for error. In anatomical pathology, the biopsies for malignancies are interpreted to confirm diagnosis and perform risk assessment, with evaluation of margins generally reserved for subsequent definitive resections. Typically, margins are not required by clinicians or reported by pathologists in common endoscopic (eg, stomach, colon) or needle core (eg, prostate, breast) biopsies. Skin holds a rather unique position in which margin evaluation is not just limited to excisions. With the exception of samples generated from electrodesiccation and curettage, it is common practice by some laboratories to report margins on most specimens of cutaneous malignancies.

In simple terms, when margins are labeled negative there should be no residual disease, and when they are deemed positive there should be disease still persisting in the patient. Margin evaluation for BCC on biopsies falls short on both fronts. In one analysis, 24% (34/143) of shave biopsies reported with negative margins displayed residual BCC in ensuing re-excisions (negative predictive value: 76%).² Standard bread-loafing, en-face margins and inking for orientation utilized to provide a thorough margin evaluation of excisions cannot be optimally achieved on small skin biopsies. Microscopic sections for analysis are 2-dimensional representations of 3-dimensional structures. Slides prepared can miss deeply embedded outermost margins, positioned parallel to the plane of sectioning, thereby creating blind spots where margins cannot be precisely assessed and generating an inherent limitation in evaluation. Exhaustive deeper levels done routinely can address this issue to a certain degree; however, it can be an impractical solution with cost implications and delay in turnaround time.

Conversely, it also is common to encounter absence of residual BCC in re-excisions in which the original biopsy margins were labeled positive. In one analysis, 49% of BCC patients (n=100) with positive biopsy margins did not display residual neoplasm on following re-excisions.³ Localized biopsy site immune response as a cause of postbiopsy regression of residual tumor has been hypothesized to produce this phenomenon. Moreover, initial biopsies may eliminate the majority of the tumor with only minimal disease persisting. Re-excisions submitted in toto allow for a systematic examination; however, areas in between sections still remain where minute residual tumor may hide. Searching for such occult foci generally is not aggressively pursued via deeper levels unless the margins of re-excision are in question.

Superficial-type BCC (or superficial multifocal BCC) is a major factor in precluding precise biopsy margin evaluation. In a study where initial biopsies reported with negative margins displayed residual BCC in subsequent re-excisions, 91% (31/34) of residual BCCs were of superficial variety.² Clinically, superficial BCC frequently has indistinct borders with subtle subclinical peripheral progression. It has a tendency to expand radially, with the clinical appearance deceptively smaller than its true extent. In a plane of histopathologic section, superficial BCC may exhibit skip zones within the epidermis. Even though the margin may seem uninvolved on the slide, a noncontiguous focus may still emerge beyond the “negative” margin. Because superficial pattern is not unusual as one of the components of mixed histology (composite) BCC, this issue is not just limited to tumors specifically designated as superficial type.⁴

The intent of a procedure is important to recognize. If a biopsy is done with the intention of diagnosis only, the pathologic assessment can be limited to tumor identification and core data elements, with margin evaluation reserved for excisions done with therapeutic intent. However, the intent is not always clear, which adds to ambiguity on when to report margins. It is not uncommon to find saucerization shaves or large punch biopsies for BCC carried out with a therapeutic intent. The status of margin is desired in such samples; however, the intent is not always clearly communicated on requisitions. To avoid any gaps in communication, some pathologists may err on the side of caution and start routinely reporting margins on biopsies.

Taking into account the inaccuracy of margin assessment in biopsies, an argument for omitting margin reporting is plausible. Although dermatologists are the major contributors of skin samples, pathology laboratories cater to a broader clientele. Other physicians from different surgical and medical specialities also perform skin biopsies, and catering to a variety of specialities adds another layer of complexity. A dermatologist may appreciate the debate regarding reliability of margins; however, a physician from another speciality who is not as familiar with the diseases of the integument may lack proper understanding. Omitting margin reporting may lead to misinterpretations or false assumptions, such as, “The margins must be uninvolved, otherwise the pathologist would have said something.” This also can generate additional phone or email inquiries and second review requests. Rather than completely omitting them, another strategy can be to report margins in more quantitative terms. One reporting approach is to have 3 categories of involved, uninvolved, and uninvolved but close for margins less than 1 mm. The cases in the third category may require greater scrutiny by deeper levels or an added caveat in the comment addressing the limitation. If the status of margins is not reported due to a certain reason, a short comment can be added to explain the reason.

In sum, clinicians should recognize that “margin negative” on skin biopsy does not always equate to “completely excised.” Margin status on biopsies is a data item that essentially provides a probability of margin clearance. Completely omitting the margin status on all biopsies may not be the most prudent approach; however, improved guidelines and modifications to enhance the reporting are definitely required.

References

1. Brady MC, Hossler EW. Reliability of biopsy margin status for basal cell carcinoma: a retrospective study. Cutis. 2020;106:315-317.
    
2. Willardson HB, Lombardo J, Raines M, et al. Predictive value of basal cell carcinoma biopsies with negative margins: a retrospective cohort study. J Am Acad Dermatol. 2018;79:42-46.
    
3. Yuan Y, Duff ML, Sammons DL, et al. Retrospective chart review of skin cancer presence in the wide excisions. World J Clin Cases. 2014;2:52-56.
    
4. Cohen PR, Schulze KE, Nelson BR. Basal cell carcinoma with mixed histology: a possible pathogenesis for recurrent skin cancer. Dermatol Surg. 2006;32:542-551.

Continue to: Author's Response...

Authors’ Response

We appreciate the thorough and thoughtful comments in the Letter to the Editor. We agree with the author’s assertion that negative margins on skin specimens does not equate to “completely excised” and that the intent of the clinician is not always clear, even when the pathologist has ready access to the clinician’s notes, as was the case for the majority of specimens included in our study.

There is already variability in how pathologists report margins, including the specific verbiage used, at least for melanocytic lesions.¹ The choice of whether or not to report margins and the meaning of those margins is complex due to the uncertainty inherent in margin assessment. Quantifying this uncertainty was the main reason for our study. Ultimately, the pathologist’s decision on whether and how to report margins should be focused on improving patient outcomes. There are benefits and drawbacks to all approaches, and our goal is to provide more information for clinicians and pathologists so that they may better care for their patients. Understanding the limitations of margins on submitted skin specimens—whether margins are reported or not—can only serve to guide improve clinical decision-making. 

We also agree that the breadth of specialties of submitting clinicians make reporting of margins difficult, and there is likely similar breadth in their understanding of the nuances of margin assessment and reports. The solution to this problem is adequate education regarding the limitations of a pathology report, and specifically what is meant when margins are (or are not) reported on skin specimens. How to best educate the myriad clinicians who submit biopsies is, of course, the ultimate challenge.

We hope that our study adds information to this ongoing debate regarding margin status reporting, and we appreciate the discussion points raised by the author.

Eric Hossler, MD; Mary Brady, MD

From the Department of Dermatology, Geisinger Health System, Danville, Pennsylvania.

The authors report no conflict of interest.

Reference

1. Sellheyer K, Bergfeld WF, Stewart E, et al. Evaluation of surgical margins in melanocytic lesions: a survey among 152 dermatopathologists.J Cutan Pathol. 2005;32:293-299.

A dermal-wounding strategy involving fractionated laser resurfacing not only treated actinic keratoses, but it prevented the development of nonmelanoma skin cancer on treated areas, according to the results of a small, randomized trial.

“Previous research suggests a new model to explain why older patients obtain nonmelanoma skin cancer in areas of ongoing sun exposure,” presenting author Jeffrey Wargo, MD, said during the annual conference of the American Society for Laser Medicine and Surgery. “Insulinlike growth factor-1 produced by dermal fibroblasts dictates how overlying skin keratinocytes respond to UVB radiation. The skin of a patient aged in their 20s produces normal levels of healthy fibroblasts, normal levels of insulinlike growth factor 1, and appropriate UVB response via activation of nucleotide excision, repair, and DNA damage checkpoint-signaling systems.”

Older patients, meanwhile, have an increase in senescent fibroblasts, decreased insulinlike growth factor-1 (IGF-1), and an inappropriate UVB response to DNA damage, continued Dr. Wargo, a dermatologist at the Ohio State University Wexner Medical Center in Columbus. Previous studies conducted by his mentor, Jeffrey B. Travers, MD, PhD, a dermatologist and pharmacologist at Wright State University, Dayton, showed that fractionated laser resurfacing (FLR) restores UVB response in older patients’ skin by resulting in new fibroblasts and increased levels of IGF 2 years post wounding.

To determine if FLR of aged skin can prevent the development of actinic keratosis (AK) and nonmelanoma skin cancer, Dr. Travers and Dr. Wargo recruited 48 patients at the Dayton VA Medical Center who were 60 years or older and had at least five AKs on each arm that were 3 mm or smaller, with nothing concerning for skin cancer at the screening visit.

Randomization of which arm was treated was based on an odd or even Social Security Number. That arm was treated with the 2,790 nm Erbium:YSSG ablative laser at 120 J/m² with one pass at 24% coverage from the elbow to hand dorsally. Previously published data reported outcomes for 30 of these patients at 3 and 6 months following treatment. Subsequent to that report, 18 additional subjects have been recruited to the study and follow-up has been extended. Of the 48 patients, 47 were male and their average age was 74, with a range between 61 and 87 years.

At 3 months following FLR, the ratio of AKs on the treated vs. untreated arms was reduced by fourfold, with a P value less than .00001^{, Dr. Wargo reported}. “Throughout the current 30-month follow-up period, this ratio has been maintained,” he said. “In fact, none of the ratios determined at 3, 6, 12, 18, 24, or 30 months post FLR are significantly different. Hence, as described in our first report on this work, these data indicate FLR is an effective treatment for existing AKs. However, our model predicts that FLR treatment will also prevent the occurrence of new AK lesions.”

Among 19 of the study participants who have been followed out to 30 months, untreated arms continued to accumulate increasing number of AKs. In contrast, AKs on treated arms are decreasing with time, indicating the lack of newly initiated lesions.

“A second analysis of the data posits that, if FLR were only removing existing lesions, one would predict the number of AKs that were present at 3 months on both the untreated and FLR-treated [arms] would accumulate at the same rate subsequent to 3 months point in time,” Dr. Wargo said.

He pointed out that 12 patients were removed from the study: two at 12 months, one at 18 months, eight at 24 months, and one at 30 months, as they were found to have 20 or more AKs on their untreated arm and required treatment.

Over the entire study period, “consistent with the notion that FLR was preventing new actinic neoplasia, we noted a dramatic difference in numbers of nonmelanoma skin cancer diagnosed in the untreated areas (22) versus FLR treated areas (2),” Dr. Wargo said. The majority of nonmelanoma skin cancers diagnosed were SCC (17) and 5 basal cell carcinomas on the untreated arms, whereas the 2 diagnosed on the treated arm were SCC. “These studies indicate that a dermal-wounding strategy involving FLR, which upregulates dermal IGF-1 levels, not only treats AKs but prevents nonmelanoma skin cancer,” he said.

The study was funded by the National Institutes of Health. Dr. Travers is the principal investigator. Dr. Wargo reported having no financial disclosures.

[email protected]

A dermal-wounding strategy involving fractionated laser resurfacing not only treated actinic keratoses, but it prevented the development of nonmelanoma skin cancer on treated areas, according to the results of a small, randomized trial.

“Previous research suggests a new model to explain why older patients obtain nonmelanoma skin cancer in areas of ongoing sun exposure,” presenting author Jeffrey Wargo, MD, said during the annual conference of the American Society for Laser Medicine and Surgery. “Insulinlike growth factor-1 produced by dermal fibroblasts dictates how overlying skin keratinocytes respond to UVB radiation. The skin of a patient aged in their 20s produces normal levels of healthy fibroblasts, normal levels of insulinlike growth factor 1, and appropriate UVB response via activation of nucleotide excision, repair, and DNA damage checkpoint-signaling systems.”

Older patients, meanwhile, have an increase in senescent fibroblasts, decreased insulinlike growth factor-1 (IGF-1), and an inappropriate UVB response to DNA damage, continued Dr. Wargo, a dermatologist at the Ohio State University Wexner Medical Center in Columbus. Previous studies conducted by his mentor, Jeffrey B. Travers, MD, PhD, a dermatologist and pharmacologist at Wright State University, Dayton, showed that fractionated laser resurfacing (FLR) restores UVB response in older patients’ skin by resulting in new fibroblasts and increased levels of IGF 2 years post wounding.

To determine if FLR of aged skin can prevent the development of actinic keratosis (AK) and nonmelanoma skin cancer, Dr. Travers and Dr. Wargo recruited 48 patients at the Dayton VA Medical Center who were 60 years or older and had at least five AKs on each arm that were 3 mm or smaller, with nothing concerning for skin cancer at the screening visit.

Randomization of which arm was treated was based on an odd or even Social Security Number. That arm was treated with the 2,790 nm Erbium:YSSG ablative laser at 120 J/m² with one pass at 24% coverage from the elbow to hand dorsally. Previously published data reported outcomes for 30 of these patients at 3 and 6 months following treatment. Subsequent to that report, 18 additional subjects have been recruited to the study and follow-up has been extended. Of the 48 patients, 47 were male and their average age was 74, with a range between 61 and 87 years.

At 3 months following FLR, the ratio of AKs on the treated vs. untreated arms was reduced by fourfold, with a P value less than .00001^{, Dr. Wargo reported}. “Throughout the current 30-month follow-up period, this ratio has been maintained,” he said. “In fact, none of the ratios determined at 3, 6, 12, 18, 24, or 30 months post FLR are significantly different. Hence, as described in our first report on this work, these data indicate FLR is an effective treatment for existing AKs. However, our model predicts that FLR treatment will also prevent the occurrence of new AK lesions.”

Among 19 of the study participants who have been followed out to 30 months, untreated arms continued to accumulate increasing number of AKs. In contrast, AKs on treated arms are decreasing with time, indicating the lack of newly initiated lesions.

“A second analysis of the data posits that, if FLR were only removing existing lesions, one would predict the number of AKs that were present at 3 months on both the untreated and FLR-treated [arms] would accumulate at the same rate subsequent to 3 months point in time,” Dr. Wargo said.

He pointed out that 12 patients were removed from the study: two at 12 months, one at 18 months, eight at 24 months, and one at 30 months, as they were found to have 20 or more AKs on their untreated arm and required treatment.

Over the entire study period, “consistent with the notion that FLR was preventing new actinic neoplasia, we noted a dramatic difference in numbers of nonmelanoma skin cancer diagnosed in the untreated areas (22) versus FLR treated areas (2),” Dr. Wargo said. The majority of nonmelanoma skin cancers diagnosed were SCC (17) and 5 basal cell carcinomas on the untreated arms, whereas the 2 diagnosed on the treated arm were SCC. “These studies indicate that a dermal-wounding strategy involving FLR, which upregulates dermal IGF-1 levels, not only treats AKs but prevents nonmelanoma skin cancer,” he said.

The study was funded by the National Institutes of Health. Dr. Travers is the principal investigator. Dr. Wargo reported having no financial disclosures.

[email protected]

A dermal-wounding strategy involving fractionated laser resurfacing not only treated actinic keratoses, but it prevented the development of nonmelanoma skin cancer on treated areas, according to the results of a small, randomized trial.

“Previous research suggests a new model to explain why older patients obtain nonmelanoma skin cancer in areas of ongoing sun exposure,” presenting author Jeffrey Wargo, MD, said during the annual conference of the American Society for Laser Medicine and Surgery. “Insulinlike growth factor-1 produced by dermal fibroblasts dictates how overlying skin keratinocytes respond to UVB radiation. The skin of a patient aged in their 20s produces normal levels of healthy fibroblasts, normal levels of insulinlike growth factor 1, and appropriate UVB response via activation of nucleotide excision, repair, and DNA damage checkpoint-signaling systems.”

Older patients, meanwhile, have an increase in senescent fibroblasts, decreased insulinlike growth factor-1 (IGF-1), and an inappropriate UVB response to DNA damage, continued Dr. Wargo, a dermatologist at the Ohio State University Wexner Medical Center in Columbus. Previous studies conducted by his mentor, Jeffrey B. Travers, MD, PhD, a dermatologist and pharmacologist at Wright State University, Dayton, showed that fractionated laser resurfacing (FLR) restores UVB response in older patients’ skin by resulting in new fibroblasts and increased levels of IGF 2 years post wounding.

To determine if FLR of aged skin can prevent the development of actinic keratosis (AK) and nonmelanoma skin cancer, Dr. Travers and Dr. Wargo recruited 48 patients at the Dayton VA Medical Center who were 60 years or older and had at least five AKs on each arm that were 3 mm or smaller, with nothing concerning for skin cancer at the screening visit.

Randomization of which arm was treated was based on an odd or even Social Security Number. That arm was treated with the 2,790 nm Erbium:YSSG ablative laser at 120 J/m² with one pass at 24% coverage from the elbow to hand dorsally. Previously published data reported outcomes for 30 of these patients at 3 and 6 months following treatment. Subsequent to that report, 18 additional subjects have been recruited to the study and follow-up has been extended. Of the 48 patients, 47 were male and their average age was 74, with a range between 61 and 87 years.

At 3 months following FLR, the ratio of AKs on the treated vs. untreated arms was reduced by fourfold, with a P value less than .00001^{, Dr. Wargo reported}. “Throughout the current 30-month follow-up period, this ratio has been maintained,” he said. “In fact, none of the ratios determined at 3, 6, 12, 18, 24, or 30 months post FLR are significantly different. Hence, as described in our first report on this work, these data indicate FLR is an effective treatment for existing AKs. However, our model predicts that FLR treatment will also prevent the occurrence of new AK lesions.”

Among 19 of the study participants who have been followed out to 30 months, untreated arms continued to accumulate increasing number of AKs. In contrast, AKs on treated arms are decreasing with time, indicating the lack of newly initiated lesions.

“A second analysis of the data posits that, if FLR were only removing existing lesions, one would predict the number of AKs that were present at 3 months on both the untreated and FLR-treated [arms] would accumulate at the same rate subsequent to 3 months point in time,” Dr. Wargo said.

He pointed out that 12 patients were removed from the study: two at 12 months, one at 18 months, eight at 24 months, and one at 30 months, as they were found to have 20 or more AKs on their untreated arm and required treatment.

Over the entire study period, “consistent with the notion that FLR was preventing new actinic neoplasia, we noted a dramatic difference in numbers of nonmelanoma skin cancer diagnosed in the untreated areas (22) versus FLR treated areas (2),” Dr. Wargo said. The majority of nonmelanoma skin cancers diagnosed were SCC (17) and 5 basal cell carcinomas on the untreated arms, whereas the 2 diagnosed on the treated arm were SCC. “These studies indicate that a dermal-wounding strategy involving FLR, which upregulates dermal IGF-1 levels, not only treats AKs but prevents nonmelanoma skin cancer,” he said.

The study was funded by the National Institutes of Health. Dr. Travers is the principal investigator. Dr. Wargo reported having no financial disclosures.

[email protected]

Just before Memorial Day, online pharmacy and lab Valisure announced that its testing had found benzene, a known carcinogen, in batches of 78 widely-available sunscreen and after-sun products. The company has petitioned the Food and Drug Administration to recall these products, which include batches from Neutrogena, Banana Boat, CVS Health, and other brands. More than three-quarters of the products are sprays.

©Vesna Andjic/iStockphoto.com

“We’re asking our patients to put sunscreen on from 6 months of age, telling them to do it their entire life, their whole body, multiple times a day,” Christopher G. Bunick, MD, PhD, associate professor of dermatology at Yale University, New Haven, Conn., said in an interview. If benzene-contaminated sunscreen proves to be a widespread problem, he said, “the benzene amounts can add up to a significant chronic exposure over a lifetime.”

In the Valisure statement announcing the findings, Dr. Bunick, who is also quoted in the petition, said that “it is critical that regulatory agencies address benzene contamination in sunscreens, and all topical medications at the manufacturing and final product level, so that all individuals feel safe using sunscreen products.”

The list of products that tested positive is included in the citizen petition, and a full list of products that did not show any contamination is available in an attachment.

Benzene is not an ingredient in sunscreen, and Valisure’s petition suggests that the findings are a result of contamination somewhere in the manufacturing process, not of product degradation.

“This isn’t a sunscreen issue, it’s a manufacturing issue,” said Adam Friedman, MD, professor and chief of dermatology at George Washington University, Washington. “We don’t want those things to be blurred.”

Assessing the risks

There is a risk of patients taking away the wrong message from these findings.

“People already have ambivalence about sunscreen, and this is just going to make that worse,” Dr. Friedman said in an interview. He pointed out that benzene is present in car exhaust, second-hand smoke, and elsewhere. Inhalation exposure has been the primary focus of toxicology investigations, as has exposure from ingesting things such as contaminated drinking water – not via topical application. “We don’t know how effectively [benzene] gets through the skin, if it gets absorbed systemically, and how that then behaves downstream,” he noted.

On the other hand, ultraviolet radiation is a well-established carcinogen. Avoiding an effective preventive measure such as sunscreen could prove more harmful than exposure to trace amounts of benzene, ultimately to be determined by the FDA.

“Just because those particular products do pose a risk, that doesn’t erase the message that sunscreens are safe and should be used,” Dr. Bunick said. “It’s not mutually exclusive.”

And then there’s the fact that the benzene contamination appears to be fairly limited. “The majority of products we tested, over 200 of them, had no detectable amounts of benzene, and uncontaminated sunscreen should certainly continue to be used,” David Light, CEO of Valisure, told this news organization.

Advising patients

With headlines blaring the news about a carcinogen in sunscreen, patients will be reaching out for advice.

“The number one question patients will have is, ‘What sunscreen do you recommend?’” said Dr. Bunick. “The answer should be to pick a sunscreen that we know wasn’t contaminated. Reassure your patient the ingredients themselves are effective and safe, and that’s not what’s leading to the contamination.”

Dr. Friedman agrees. “We need to be mindful. Dermatologists need to be armed with the facts in order to counsel patients: Sunscreen is still a very important, effective, and safe, scientifically based way to prevent the harmful effects of the sun, in addition to things like sun protective clothing and seeking shade between 10 a.m. and 4 p.m.”

As alarming as Valisure’s findings may seem initially, Dr. Bunick noted a silver lining. “The consumer, the public should feel reassured this report is out there. It shows that someone’s watching out. That’s an important safety message: These things aren’t going undetected.”
 

Just before Memorial Day, online pharmacy and lab Valisure announced that its testing had found benzene, a known carcinogen, in batches of 78 widely-available sunscreen and after-sun products. The company has petitioned the Food and Drug Administration to recall these products, which include batches from Neutrogena, Banana Boat, CVS Health, and other brands. More than three-quarters of the products are sprays.

©Vesna Andjic/iStockphoto.com

“We’re asking our patients to put sunscreen on from 6 months of age, telling them to do it their entire life, their whole body, multiple times a day,” Christopher G. Bunick, MD, PhD, associate professor of dermatology at Yale University, New Haven, Conn., said in an interview. If benzene-contaminated sunscreen proves to be a widespread problem, he said, “the benzene amounts can add up to a significant chronic exposure over a lifetime.”

In the Valisure statement announcing the findings, Dr. Bunick, who is also quoted in the petition, said that “it is critical that regulatory agencies address benzene contamination in sunscreens, and all topical medications at the manufacturing and final product level, so that all individuals feel safe using sunscreen products.”

The list of products that tested positive is included in the citizen petition, and a full list of products that did not show any contamination is available in an attachment.

Benzene is not an ingredient in sunscreen, and Valisure’s petition suggests that the findings are a result of contamination somewhere in the manufacturing process, not of product degradation.

“This isn’t a sunscreen issue, it’s a manufacturing issue,” said Adam Friedman, MD, professor and chief of dermatology at George Washington University, Washington. “We don’t want those things to be blurred.”

Assessing the risks

There is a risk of patients taking away the wrong message from these findings.

“People already have ambivalence about sunscreen, and this is just going to make that worse,” Dr. Friedman said in an interview. He pointed out that benzene is present in car exhaust, second-hand smoke, and elsewhere. Inhalation exposure has been the primary focus of toxicology investigations, as has exposure from ingesting things such as contaminated drinking water – not via topical application. “We don’t know how effectively [benzene] gets through the skin, if it gets absorbed systemically, and how that then behaves downstream,” he noted.

On the other hand, ultraviolet radiation is a well-established carcinogen. Avoiding an effective preventive measure such as sunscreen could prove more harmful than exposure to trace amounts of benzene, ultimately to be determined by the FDA.

“Just because those particular products do pose a risk, that doesn’t erase the message that sunscreens are safe and should be used,” Dr. Bunick said. “It’s not mutually exclusive.”

And then there’s the fact that the benzene contamination appears to be fairly limited. “The majority of products we tested, over 200 of them, had no detectable amounts of benzene, and uncontaminated sunscreen should certainly continue to be used,” David Light, CEO of Valisure, told this news organization.

Advising patients

With headlines blaring the news about a carcinogen in sunscreen, patients will be reaching out for advice.

“The number one question patients will have is, ‘What sunscreen do you recommend?’” said Dr. Bunick. “The answer should be to pick a sunscreen that we know wasn’t contaminated. Reassure your patient the ingredients themselves are effective and safe, and that’s not what’s leading to the contamination.”

Dr. Friedman agrees. “We need to be mindful. Dermatologists need to be armed with the facts in order to counsel patients: Sunscreen is still a very important, effective, and safe, scientifically based way to prevent the harmful effects of the sun, in addition to things like sun protective clothing and seeking shade between 10 a.m. and 4 p.m.”

As alarming as Valisure’s findings may seem initially, Dr. Bunick noted a silver lining. “The consumer, the public should feel reassured this report is out there. It shows that someone’s watching out. That’s an important safety message: These things aren’t going undetected.”
 

Just before Memorial Day, online pharmacy and lab Valisure announced that its testing had found benzene, a known carcinogen, in batches of 78 widely-available sunscreen and after-sun products. The company has petitioned the Food and Drug Administration to recall these products, which include batches from Neutrogena, Banana Boat, CVS Health, and other brands. More than three-quarters of the products are sprays.

©Vesna Andjic/iStockphoto.com

“We’re asking our patients to put sunscreen on from 6 months of age, telling them to do it their entire life, their whole body, multiple times a day,” Christopher G. Bunick, MD, PhD, associate professor of dermatology at Yale University, New Haven, Conn., said in an interview. If benzene-contaminated sunscreen proves to be a widespread problem, he said, “the benzene amounts can add up to a significant chronic exposure over a lifetime.”

In the Valisure statement announcing the findings, Dr. Bunick, who is also quoted in the petition, said that “it is critical that regulatory agencies address benzene contamination in sunscreens, and all topical medications at the manufacturing and final product level, so that all individuals feel safe using sunscreen products.”

The list of products that tested positive is included in the citizen petition, and a full list of products that did not show any contamination is available in an attachment.

Benzene is not an ingredient in sunscreen, and Valisure’s petition suggests that the findings are a result of contamination somewhere in the manufacturing process, not of product degradation.

“This isn’t a sunscreen issue, it’s a manufacturing issue,” said Adam Friedman, MD, professor and chief of dermatology at George Washington University, Washington. “We don’t want those things to be blurred.”

Assessing the risks

There is a risk of patients taking away the wrong message from these findings.

“People already have ambivalence about sunscreen, and this is just going to make that worse,” Dr. Friedman said in an interview. He pointed out that benzene is present in car exhaust, second-hand smoke, and elsewhere. Inhalation exposure has been the primary focus of toxicology investigations, as has exposure from ingesting things such as contaminated drinking water – not via topical application. “We don’t know how effectively [benzene] gets through the skin, if it gets absorbed systemically, and how that then behaves downstream,” he noted.

On the other hand, ultraviolet radiation is a well-established carcinogen. Avoiding an effective preventive measure such as sunscreen could prove more harmful than exposure to trace amounts of benzene, ultimately to be determined by the FDA.

“Just because those particular products do pose a risk, that doesn’t erase the message that sunscreens are safe and should be used,” Dr. Bunick said. “It’s not mutually exclusive.”

And then there’s the fact that the benzene contamination appears to be fairly limited. “The majority of products we tested, over 200 of them, had no detectable amounts of benzene, and uncontaminated sunscreen should certainly continue to be used,” David Light, CEO of Valisure, told this news organization.

Advising patients

With headlines blaring the news about a carcinogen in sunscreen, patients will be reaching out for advice.

“The number one question patients will have is, ‘What sunscreen do you recommend?’” said Dr. Bunick. “The answer should be to pick a sunscreen that we know wasn’t contaminated. Reassure your patient the ingredients themselves are effective and safe, and that’s not what’s leading to the contamination.”

Dr. Friedman agrees. “We need to be mindful. Dermatologists need to be armed with the facts in order to counsel patients: Sunscreen is still a very important, effective, and safe, scientifically based way to prevent the harmful effects of the sun, in addition to things like sun protective clothing and seeking shade between 10 a.m. and 4 p.m.”

As alarming as Valisure’s findings may seem initially, Dr. Bunick noted a silver lining. “The consumer, the public should feel reassured this report is out there. It shows that someone’s watching out. That’s an important safety message: These things aren’t going undetected.”
 

Within the last decade, almost 3000 articles have been published on the role of diet in the prevention and management of dermatologic conditions. Patients are increasingly interested in—and employing—dietary modifications that may influence skin appearance and aid in the treatment of cutaneous disease.¹ It is essential that dermatologists are familiar with existing evidence on the role of diet in dermatology to counsel patients appropriately. Herein, we discuss the compositions of several popular diets and their proposed utility for dermatologic purposes. We highlight the limited literature that exists surrounding this topic and emphasize the need for future, well-designed clinical trials that study the impact of diet on skin disease.

Ketogenic Diet

The ketogenic diet has a macronutrient profile composed of high fat, low to moderate protein, and very low carbohydrates. Nutritional ketosis occurs as the body begins to use free fatty acids (via beta oxidation) as the primary metabolite driving cellular metabolism. It has been suggested that the ketogenic diet may impart beneficial effects on skin disease; however, limited literature exists on the role of nutritional ketosis in the treatment of dermatologic conditions.

Mechanistically, the ketogenic diet decreases the secretion of insulin and insulinlike growth factor 1, resulting in a reduction of circulating androgens and increased activity of the retinoid X receptor.² In acne vulgaris, it has been suggested that the ketogenic diet may be beneficial in decreasing androgen-induced sebum production and the overproliferation of keratinocytes.^2-7 The ketogenic diet is one of the most rapidly effective dietary strategies for normalizing both insulin and androgens, thus it may theoretically be useful for other metabolic and hormone-dependent skin diseases, such as hidradenitis suppurativa.^8,9

The cutaneous manifestations associated with chronic hyperinsulinemia and hyperglycemia are numerous and include acanthosis nigricans, acrochordons, diabetic dermopathy, scleredema diabeticorum, bullosis diabeticorum, keratosis pilaris, and generalized granuloma annulare. There also is an increased risk for bacterial and fungal skin infections associated with hyperglycemic states.¹⁰ The ketogenic diet is an effective nonpharmacologic tool for normalizing serum insulin and glucose levels in most patients and may have utility in the aforementioned conditions.^11,12 In addition to improving insulin sensitivity, it has been used as a dietary strategy for weight loss.^11-15 Because obesity and metabolic syndrome are highly correlated with common skin conditions such as psoriasis, hidradenitis suppurativa, and androgenetic alopecia, there may be a role for employing the ketogenic diet in these patient populations.^16,17

Although robust clinical studies on ketogenic diets in skin disease are lacking, a recent single-arm, open-label clinical trial observed benefit in all 37 drug-naïve, overweight patients with chronic plaque psoriasis who underwent a ketogenic weight loss protocol. Significant reductions in psoriasis area and severity index (PASI) score and dermatology life quality index score were reported (P<.001).¹⁸ Another study of 30 patients with psoriasis found that a 4-week, low-calorie, ketogenic diet resulted in 50% improvement of PASI scores, 10% weight loss, and a reduction in the proinflammatory cytokines IL-1β and IL-2.¹⁹ Despite these results, it is a challenge to tease out if the specific dietary intervention or its associated weight loss was the main driver in these reported improvements in skin disease.

There is mixed evidence on the anti-inflammatory nature of the ketogenic diet, likely due to wide variation in the composition of foods included in individual diets. In many instances, the ketogenic diet is thought to possess considerable antioxidant and anti-inflammatory capabilities. Ketones are known activators of the nuclear factor erythroid 2–related factor 2 pathway, which upregulates the production of glutathione, a major endogenous intracellular antioxidant.²⁰ Additionally, dietary compounds from foods that are encouraged while on the ketogenic diet, such as sulforaphane from broccoli, also are independent activators of nuclear factor erythroid 2–related factor 2.²¹ Ketones are efficiently utilized by mitochondria, which also may result in the decreased production of reactive oxygen species and lower oxidative stress.²² Moreover, the ketone body β-hydroxybutyrate has demonstrated the ability to reduce proinflammatory IL-1β levels via suppression of nucleotide-binding domain-like receptor protein 3 inflammasome activity.^23,24 The activity of IL-1β is known to be elevated in many dermatologic conditions, including juvenile idiopathic arthritis, relapsing polychondritis, Schnitzler syndrome, hidradenitis suppurativa, Behçet disease, and other autoinflammatory syndromes.²⁵ Ketones also have been shown to inhibit the nuclear factor–κB proinflammatory signaling pathway.^22,26,27 Overexpression of IL-1β and aberrant activation of nuclear factor–κB are implicated in a variety of inflammatory, autoimmune, and oncologic cutaneous pathologies. The ketogenic diet may prove to be an effective adjunctive treatment for dermatologists to consider in select patient populations.^23,24,28-30

For patients with keratinocyte carcinomas, the ketogenic diet may offer the aforementioned anti-inflammatory and antioxidant effects, as well as suppression of the mechanistic target of rapamycin, a major regulator of cell metabolism and proliferation.^31,32 Inhibition of mechanistic target of rapamycin activity has been shown to slow tumor growth and reduce the development of squamous cell carcinoma.^25,33,34 The ketogenic diet also may exploit the preferential utilization of glucose exhibited by many types of cancer cells, thereby “starving” the tumor of its primary fuel source.^35,36 In vitro and animal studies in a variety of cancer types have demonstrated that a ketogenic metabolic state—achieved through the ketogenic diet or fasting—can sensitize tumor cells to chemotherapy and radiation while conferring a protective effect to normal cells.^37-40 This recently described phenomenon is known as differential stress resistance, but it has not been studied in keratinocyte malignancies or melanoma to date. Importantly, some basal cell carcinomas and BRAF V600E–mutated melanomas have worsened while on the ketogenic diet, suggesting more data is needed before it can be recommended for all cancer patients.^41,42 Furthermore, other skin conditions such as prurigo pigmentosa have been associated with initiation of the ketogenic diet.⁴³

Low FODMAP Diet

Fermentable oligosaccharides, disaccharides, monosaccharides, and polyols (FODMAPs) are short-chain carbohydrates that are poorly absorbed, osmotically active, and rapidly fermented by intestinal bacteria.⁴⁴ The low FODMAP diet has been shown to be efficacious for treatment of irritable bowel syndrome, small intestinal bacterial overgrowth (SIBO), and some cases of inflammatory bowel disease (IBD).^44-49 A low FODMAP diet may have potential implications for several dermatologic conditions.

Rosacea has been associated with various gastrointestinal tract disorders including irritable bowel syndrome, SIBO, and IBD.^50-54 A single study found that patients with rosacea had a 13-fold increased risk for SIBO.^55,56 Treatment of 40 patients with SIBO using rifaximin resulted in complete resolution of rosacea in all patients, with no relapse after a 3-year follow-up period.⁵⁵ Psoriasis also has been associated with SIBO and IBD.^57,58 One small study found that eradication of SIBO in psoriatic patients resulted in improved PASI scores and colorimetric values.⁵⁹

Although the long-term health consequences of the low FODMAP diet are unknown, further research on such dietary interventions for inflammatory skin conditions is warranted given the mounting evidence of a gut-skin connection and the role of the intestinal microbiome in skin health.^50,51

Gluten-Free Diet

Gluten is a protein found in a variety of grains. Although the role of gluten in the pathogenesis of celiac disease and dermatitis herpetiformis is indisputable, the deleterious effects of gluten outside of the context of these diseases remain controversial. There may be a compelling case for eliminating gluten in psoriasis patients with seropositivity for celiac disease. A recent systematic review found a 2.2-fold increased risk for celiac disease in psoriasis patients.⁶⁰ Antigliadin antibody titers also were found to be positively correlated with psoriatic disease severity.⁶¹ In addition, one open-label study found a reduction in PASI scores in 73% of patients with antigliadin antibodies after 3 months on a gluten-free diet compared to those without antibodies; however, the study only included 22 patients.⁶² Several other small studies have yielded similar results^63,64; however, antigliadin antibodies are neither the most sensitive nor specific markers of celiac disease, and additional testing should be completed in any patient who may carry this diagnosis. A survey study by the National Psoriasis Foundation found that the dietary change associated with the greatest skin improvement was removal of gluten and nightshade vegetables in approximately 50% of the 1200 psoriasis patients that responded.⁶⁵ Case reports of various dermatologic conditions including sarcoidosis, vitiligo, alopecia areata, lichen planus, dermatomyositis, pyoderma gangrenosum, erythema nodosum, leukocytoclastic vasculitis, linear IgA bullous dermatosis, and aphthous ulcerations have reportedly improved with a gluten-free diet; however, this should not be used as primary therapy in patients without celiac disease.^66-71 Because gluten-free diets can be expensive and challenging to follow, a formal assessment for celiac disease should be considered before recommendation of this dietary intervention.

Low Histamine Diet

Histamine is a biogenic amine produced by the decarboxylation of the amino acid histidine.⁷² It is found in several foods in varying amounts. Because bacteria can convert histidine into histamine, many fermented and aged foods such as kimchi, sauerkraut, cheese, and red wine contain high levels of histamine. Individuals who have decreased activity of diamine oxidase (DAO), an enzyme that degrades histamine, may be more susceptible to histamine intolerance.⁷² The symptoms of histamine intolerance are numerous and include gastrointestinal tract distress, rhinorrhea and nasal congestion, headache, urticaria, flushing, and pruritus. Histamine intolerance can mimic an IgE-mediated food allergy; however, allergy testing is negative in these patients. Unfortunately, there is no laboratory test for histamine intolerance; a double-blind, placebo-controlled food challenge is considered the gold-standard test.⁷²

As it pertains to dermatology, a low histamine diet may play a role in the treatment of certain patients with atopic dermatitis and chronic spontaneous urticaria. One study reported that 17 of 54 (31.5%) atopic patients had higher basal levels of serum histamine compared to controls.⁷³ Another study found that a histamine-free diet led to improvement in both histamine intolerance symptoms and atopic dermatitis disease severity (SCORing atopic dermatitis) in patients with low DAO activity.⁷⁴ In chronic spontaneous urticaria, a recent systematic review found that in 223 patients placed on a low histamine diet for 3 to 4 weeks, 12% and 44% achieved complete and partial remission, respectively.⁷⁵ Although treatment response based on a patient’s DAO activity level has not been correlated, a diet low in histamine may prove useful for patients with persistent atopic dermatitis and chronic spontaneous urticaria who have negative food allergy tests and report exacerbation of symptoms after ingestion of histamine-rich foods.^76,77

Mediterranean Diet

The Mediterranean diet has been touted as one of the healthiest diets to date, and large randomized clinical trials have demonstrated its effectiveness in weight loss, improving insulin sensitivity, and reducing inflammatory cytokine profiles.^78,79 A major criticism of the Mediterranean diet is that it has considerable ambiguity and lacks a precise definition due to the variability of what is consumed in different Mediterranean regions. Generally, the diet emphasizes high consumption of colorful fruits and vegetables, aromatic herbs and spices, olive oil, nuts, and seafood, as well as modest amounts of dairy, eggs, and red meat.⁸⁰ The anti-inflammatory effects of this diet largely have been attributed to its abundance of polyphenols, carotenoids, monounsaturated fatty acids, and omega-3 polyunsaturated fatty acids (PUFAs).^80,81 Examples of polyphenols include resveratrol in red grapes, quercetin in apples and red onions, and curcumin in turmeric, while examples of carotenoids include lycopene in tomatoes and zeaxanthin in dark leafy greens. Oleic acid is a monounsaturated fatty acid present in high concentrations in olive oil, while eicosapentaenoic acid and docosahexaenoic acid are omega-3 PUFAs predominantly found in fish.⁸²

Unfortunately, rigorous clinical trials regarding the Mediterranean diet as it pertains to dermatology have not been undertaken. Numerous observational studies in patients with psoriasis have suggested that close adherence to the Mediterranean diet was associated with improvement in PASI scores.^83-86 The National Psoriasis Foundation now recommends a trial of the Mediterranean diet in some patients with psoriasis, emphasizing increased dietary intake of olive oil, fish, and vegetables.⁸⁷ Adherence to a Mediterranean diet also has been inversely correlated to the severity of acne vulgaris and hidradenitis suppurativa^88,89; however, these studies failed to account for the multifactorial risk factors associated with these conditions. Mediterranean diets also may impart a chemopreventive effect, supported by a number of in vivo and in vitro studies demonstrating the inhibition and/or reversal of cutaneous DNA damage induced by UV radiation through supplementation with various phytonutrients and omega-3 PUFAs.^81,90-92 Although small case-control studies have found a decreased risk of basal cell carcinoma in those who closely adhered to a Mediterranean diet, more rigorous clinical research is needed.⁹³

Whole-Food, Plant-Based Diet

A whole-food, plant-based (WFPB) diet is another popular dietary approach that consists of eating fruits, vegetables, legumes, nuts, seeds, and grains in their whole natural form.⁹⁴ This diet discourages all animal products, including red meat, seafood, dairy, and eggs. It is similar to a vegan diet except that it eliminates all highly refined carbohydrates, vegetable oils, and other processed foods.⁹⁴ Randomized clinical studies have demonstrated the WFPB diet to be effective in the treatment of obesity and metabolic syndrome.^95,96

A WFPB diet has been shown to increase the antioxidant capacity of cells, lengthen telomeres, and reduce formation of advanced glycation end products.^94,97,98 These benefits may help combat accelerated skin aging, including increased skin permeability, reduced elasticity and hydration, decreased angiogenesis, impaired immune function, and decreased vitamin D synthesis. Accelerated skin aging can result in delayed wound healing and susceptibility to skin tears and ecchymoses and also may promote the development of cutaneous malignancies.⁹⁹ There remains a lack of clinical data studying a properly formulated WFPB diet in the dermatologic setting.

Paleolithic Diet

The paleolithic (Paleo) diet is an increasingly popular way of eating that attempts to mirror what our ancestors may have consumed between 10,000 and 2.5 million years ago.¹⁰⁰ It is similar to the Mediterranean diet but excludes grains, dairy, legumes, and nightshade vegetables. It also calls for elimination of highly processed sugars and oils as well as chemical food additives and preservatives. There is a strict variation of the diet for individuals with autoimmune disease that also excludes eggs, nuts, and seeds, as these can be inflammatory or immunogenic in some patients.^100-106 Other variations of the diet exist, including the ketogenic Paleo diet, pegan (Paleo vegan) diet, and lacto-Paleo diet.¹⁰⁰ An often cited criticism of the Paleo diet is the low intake of calcium and risk for osteoporosis; however, consumption of calcium-rich foods or a calcium supplement can address this concern.¹⁰⁷

Although small clinical studies have found the Paleo diet to be beneficial for various autoimmune diseases, clinical data evaluating the utility of the diet for cutaneous disease is lacking.^108,109 Numerous randomized trials have demonstrated the Paleo diet to be effective for weight loss and improving insulin sensitivity and lipid levels.^110-116 Thus, the Paleo diet may theoretically serve as a viable adjunct dietary approach to the treatment of cutaneous diseases associated with obesity and metabolic derangement.¹¹⁷

Carnivore Diet

Arguably the most controversial and radical diet is the carnivore diet. As the name implies, the carnivore diet is based on consuming solely animal products. A properly structured carnivore diet emphasizes a “nose-to-tail” eating approach where all parts of the animal including the muscle meats, organs, and fat are consumed. Proponents of the diet cite anthropologic evidence from fossil-stable carbon-13/carbon-12 isotope analyses, craniodental features, and numerous other adaptations that indicate increased consumption of meat during human evolution.^118-122 Notably, many early humans ate a carnivore diet, but life span was very short at this time, suggesting the diet may not be as beneficial as has been suggested.

Despite the abundance of anecdotal evidence supporting its use for a variety of chronic conditions, including cutaneous autoimmune disease, there is a virtual absence of high-quality research on the carnivore diet.^123-125

The purported benefits of the carnivore diet may be attributed to the consumption of organ meats that contain highly bioavailable essential vitamins and minerals, such as iron, zinc, copper, selenium, thiamine, niacin, folate, vitamin B₆, vitamin B₁₂, vitamin A, vitamin D, vitamin K, and choline.^126-128 Other dietary compounds that have demonstrated benefit for skin health and are predominantly found in animal foods include carnosine, carnitine, creatine, taurine, coenzyme Q10, and collagen.^129-134 Nevertheless, there is no data to recommend the elimination of antioxidant- and micronutrient-dense plant-based foods. Rigorous clinical research evaluating the efficacy and safety of the carnivore diet in dermatologic patients is needed. A carnivore diet should not be undertaken without the assistance of a dietician who can ensure adequate micronutrient and macronutrient support.

Final Thoughts

The adjunctive role of diet in the treatment of skin disease is expanding and becoming more widely accepted among dermatologists. Unfortunately, there remains a lack of randomized controlled trials confirming the efficacy of various dietary interventions in the dermatologic setting. Although evidence-based dietary recommendations currently are limited, it is important for dermatologists to be aware of the varied and nuanced dietary interventions employed by patients.

Ultimately, dietary recommendations must be personalized, considering a patient’s comorbidities, personal beliefs and preferences, and nutrigenetics. The emerging field of dermatonutrigenomics—the study of how dietary compounds interact with one’s genes to influence skin health—may allow for precise dietary recommendations to be made in dermatologic practice. Direct-to-consumer genetic tests targeted toward dermatology patients are already on the market, but their clinical utility awaits validation.¹ Because nutritional science is a constantly evolving field, becoming familiar with these popular diets will serve both dermatologists and their patients well.

Within the last decade, almost 3000 articles have been published on the role of diet in the prevention and management of dermatologic conditions. Patients are increasingly interested in—and employing—dietary modifications that may influence skin appearance and aid in the treatment of cutaneous disease.¹ It is essential that dermatologists are familiar with existing evidence on the role of diet in dermatology to counsel patients appropriately. Herein, we discuss the compositions of several popular diets and their proposed utility for dermatologic purposes. We highlight the limited literature that exists surrounding this topic and emphasize the need for future, well-designed clinical trials that study the impact of diet on skin disease.

Ketogenic Diet

The ketogenic diet has a macronutrient profile composed of high fat, low to moderate protein, and very low carbohydrates. Nutritional ketosis occurs as the body begins to use free fatty acids (via beta oxidation) as the primary metabolite driving cellular metabolism. It has been suggested that the ketogenic diet may impart beneficial effects on skin disease; however, limited literature exists on the role of nutritional ketosis in the treatment of dermatologic conditions.

Mechanistically, the ketogenic diet decreases the secretion of insulin and insulinlike growth factor 1, resulting in a reduction of circulating androgens and increased activity of the retinoid X receptor.² In acne vulgaris, it has been suggested that the ketogenic diet may be beneficial in decreasing androgen-induced sebum production and the overproliferation of keratinocytes.^2-7 The ketogenic diet is one of the most rapidly effective dietary strategies for normalizing both insulin and androgens, thus it may theoretically be useful for other metabolic and hormone-dependent skin diseases, such as hidradenitis suppurativa.^8,9

The cutaneous manifestations associated with chronic hyperinsulinemia and hyperglycemia are numerous and include acanthosis nigricans, acrochordons, diabetic dermopathy, scleredema diabeticorum, bullosis diabeticorum, keratosis pilaris, and generalized granuloma annulare. There also is an increased risk for bacterial and fungal skin infections associated with hyperglycemic states.¹⁰ The ketogenic diet is an effective nonpharmacologic tool for normalizing serum insulin and glucose levels in most patients and may have utility in the aforementioned conditions.^11,12 In addition to improving insulin sensitivity, it has been used as a dietary strategy for weight loss.^11-15 Because obesity and metabolic syndrome are highly correlated with common skin conditions such as psoriasis, hidradenitis suppurativa, and androgenetic alopecia, there may be a role for employing the ketogenic diet in these patient populations.^16,17

Although robust clinical studies on ketogenic diets in skin disease are lacking, a recent single-arm, open-label clinical trial observed benefit in all 37 drug-naïve, overweight patients with chronic plaque psoriasis who underwent a ketogenic weight loss protocol. Significant reductions in psoriasis area and severity index (PASI) score and dermatology life quality index score were reported (P<.001).¹⁸ Another study of 30 patients with psoriasis found that a 4-week, low-calorie, ketogenic diet resulted in 50% improvement of PASI scores, 10% weight loss, and a reduction in the proinflammatory cytokines IL-1β and IL-2.¹⁹ Despite these results, it is a challenge to tease out if the specific dietary intervention or its associated weight loss was the main driver in these reported improvements in skin disease.

There is mixed evidence on the anti-inflammatory nature of the ketogenic diet, likely due to wide variation in the composition of foods included in individual diets. In many instances, the ketogenic diet is thought to possess considerable antioxidant and anti-inflammatory capabilities. Ketones are known activators of the nuclear factor erythroid 2–related factor 2 pathway, which upregulates the production of glutathione, a major endogenous intracellular antioxidant.²⁰ Additionally, dietary compounds from foods that are encouraged while on the ketogenic diet, such as sulforaphane from broccoli, also are independent activators of nuclear factor erythroid 2–related factor 2.²¹ Ketones are efficiently utilized by mitochondria, which also may result in the decreased production of reactive oxygen species and lower oxidative stress.²² Moreover, the ketone body β-hydroxybutyrate has demonstrated the ability to reduce proinflammatory IL-1β levels via suppression of nucleotide-binding domain-like receptor protein 3 inflammasome activity.^23,24 The activity of IL-1β is known to be elevated in many dermatologic conditions, including juvenile idiopathic arthritis, relapsing polychondritis, Schnitzler syndrome, hidradenitis suppurativa, Behçet disease, and other autoinflammatory syndromes.²⁵ Ketones also have been shown to inhibit the nuclear factor–κB proinflammatory signaling pathway.^22,26,27 Overexpression of IL-1β and aberrant activation of nuclear factor–κB are implicated in a variety of inflammatory, autoimmune, and oncologic cutaneous pathologies. The ketogenic diet may prove to be an effective adjunctive treatment for dermatologists to consider in select patient populations.^23,24,28-30

For patients with keratinocyte carcinomas, the ketogenic diet may offer the aforementioned anti-inflammatory and antioxidant effects, as well as suppression of the mechanistic target of rapamycin, a major regulator of cell metabolism and proliferation.^31,32 Inhibition of mechanistic target of rapamycin activity has been shown to slow tumor growth and reduce the development of squamous cell carcinoma.^25,33,34 The ketogenic diet also may exploit the preferential utilization of glucose exhibited by many types of cancer cells, thereby “starving” the tumor of its primary fuel source.^35,36 In vitro and animal studies in a variety of cancer types have demonstrated that a ketogenic metabolic state—achieved through the ketogenic diet or fasting—can sensitize tumor cells to chemotherapy and radiation while conferring a protective effect to normal cells.^37-40 This recently described phenomenon is known as differential stress resistance, but it has not been studied in keratinocyte malignancies or melanoma to date. Importantly, some basal cell carcinomas and BRAF V600E–mutated melanomas have worsened while on the ketogenic diet, suggesting more data is needed before it can be recommended for all cancer patients.^41,42 Furthermore, other skin conditions such as prurigo pigmentosa have been associated with initiation of the ketogenic diet.⁴³

Low FODMAP Diet

Fermentable oligosaccharides, disaccharides, monosaccharides, and polyols (FODMAPs) are short-chain carbohydrates that are poorly absorbed, osmotically active, and rapidly fermented by intestinal bacteria.⁴⁴ The low FODMAP diet has been shown to be efficacious for treatment of irritable bowel syndrome, small intestinal bacterial overgrowth (SIBO), and some cases of inflammatory bowel disease (IBD).^44-49 A low FODMAP diet may have potential implications for several dermatologic conditions.

Rosacea has been associated with various gastrointestinal tract disorders including irritable bowel syndrome, SIBO, and IBD.^50-54 A single study found that patients with rosacea had a 13-fold increased risk for SIBO.^55,56 Treatment of 40 patients with SIBO using rifaximin resulted in complete resolution of rosacea in all patients, with no relapse after a 3-year follow-up period.⁵⁵ Psoriasis also has been associated with SIBO and IBD.^57,58 One small study found that eradication of SIBO in psoriatic patients resulted in improved PASI scores and colorimetric values.⁵⁹

Although the long-term health consequences of the low FODMAP diet are unknown, further research on such dietary interventions for inflammatory skin conditions is warranted given the mounting evidence of a gut-skin connection and the role of the intestinal microbiome in skin health.^50,51

Gluten-Free Diet

Gluten is a protein found in a variety of grains. Although the role of gluten in the pathogenesis of celiac disease and dermatitis herpetiformis is indisputable, the deleterious effects of gluten outside of the context of these diseases remain controversial. There may be a compelling case for eliminating gluten in psoriasis patients with seropositivity for celiac disease. A recent systematic review found a 2.2-fold increased risk for celiac disease in psoriasis patients.⁶⁰ Antigliadin antibody titers also were found to be positively correlated with psoriatic disease severity.⁶¹ In addition, one open-label study found a reduction in PASI scores in 73% of patients with antigliadin antibodies after 3 months on a gluten-free diet compared to those without antibodies; however, the study only included 22 patients.⁶² Several other small studies have yielded similar results^63,64; however, antigliadin antibodies are neither the most sensitive nor specific markers of celiac disease, and additional testing should be completed in any patient who may carry this diagnosis. A survey study by the National Psoriasis Foundation found that the dietary change associated with the greatest skin improvement was removal of gluten and nightshade vegetables in approximately 50% of the 1200 psoriasis patients that responded.⁶⁵ Case reports of various dermatologic conditions including sarcoidosis, vitiligo, alopecia areata, lichen planus, dermatomyositis, pyoderma gangrenosum, erythema nodosum, leukocytoclastic vasculitis, linear IgA bullous dermatosis, and aphthous ulcerations have reportedly improved with a gluten-free diet; however, this should not be used as primary therapy in patients without celiac disease.^66-71 Because gluten-free diets can be expensive and challenging to follow, a formal assessment for celiac disease should be considered before recommendation of this dietary intervention.

Low Histamine Diet

Histamine is a biogenic amine produced by the decarboxylation of the amino acid histidine.⁷² It is found in several foods in varying amounts. Because bacteria can convert histidine into histamine, many fermented and aged foods such as kimchi, sauerkraut, cheese, and red wine contain high levels of histamine. Individuals who have decreased activity of diamine oxidase (DAO), an enzyme that degrades histamine, may be more susceptible to histamine intolerance.⁷² The symptoms of histamine intolerance are numerous and include gastrointestinal tract distress, rhinorrhea and nasal congestion, headache, urticaria, flushing, and pruritus. Histamine intolerance can mimic an IgE-mediated food allergy; however, allergy testing is negative in these patients. Unfortunately, there is no laboratory test for histamine intolerance; a double-blind, placebo-controlled food challenge is considered the gold-standard test.⁷²

As it pertains to dermatology, a low histamine diet may play a role in the treatment of certain patients with atopic dermatitis and chronic spontaneous urticaria. One study reported that 17 of 54 (31.5%) atopic patients had higher basal levels of serum histamine compared to controls.⁷³ Another study found that a histamine-free diet led to improvement in both histamine intolerance symptoms and atopic dermatitis disease severity (SCORing atopic dermatitis) in patients with low DAO activity.⁷⁴ In chronic spontaneous urticaria, a recent systematic review found that in 223 patients placed on a low histamine diet for 3 to 4 weeks, 12% and 44% achieved complete and partial remission, respectively.⁷⁵ Although treatment response based on a patient’s DAO activity level has not been correlated, a diet low in histamine may prove useful for patients with persistent atopic dermatitis and chronic spontaneous urticaria who have negative food allergy tests and report exacerbation of symptoms after ingestion of histamine-rich foods.^76,77

Mediterranean Diet

The Mediterranean diet has been touted as one of the healthiest diets to date, and large randomized clinical trials have demonstrated its effectiveness in weight loss, improving insulin sensitivity, and reducing inflammatory cytokine profiles.^78,79 A major criticism of the Mediterranean diet is that it has considerable ambiguity and lacks a precise definition due to the variability of what is consumed in different Mediterranean regions. Generally, the diet emphasizes high consumption of colorful fruits and vegetables, aromatic herbs and spices, olive oil, nuts, and seafood, as well as modest amounts of dairy, eggs, and red meat.⁸⁰ The anti-inflammatory effects of this diet largely have been attributed to its abundance of polyphenols, carotenoids, monounsaturated fatty acids, and omega-3 polyunsaturated fatty acids (PUFAs).^80,81 Examples of polyphenols include resveratrol in red grapes, quercetin in apples and red onions, and curcumin in turmeric, while examples of carotenoids include lycopene in tomatoes and zeaxanthin in dark leafy greens. Oleic acid is a monounsaturated fatty acid present in high concentrations in olive oil, while eicosapentaenoic acid and docosahexaenoic acid are omega-3 PUFAs predominantly found in fish.⁸²

Unfortunately, rigorous clinical trials regarding the Mediterranean diet as it pertains to dermatology have not been undertaken. Numerous observational studies in patients with psoriasis have suggested that close adherence to the Mediterranean diet was associated with improvement in PASI scores.^83-86 The National Psoriasis Foundation now recommends a trial of the Mediterranean diet in some patients with psoriasis, emphasizing increased dietary intake of olive oil, fish, and vegetables.⁸⁷ Adherence to a Mediterranean diet also has been inversely correlated to the severity of acne vulgaris and hidradenitis suppurativa^88,89; however, these studies failed to account for the multifactorial risk factors associated with these conditions. Mediterranean diets also may impart a chemopreventive effect, supported by a number of in vivo and in vitro studies demonstrating the inhibition and/or reversal of cutaneous DNA damage induced by UV radiation through supplementation with various phytonutrients and omega-3 PUFAs.^81,90-92 Although small case-control studies have found a decreased risk of basal cell carcinoma in those who closely adhered to a Mediterranean diet, more rigorous clinical research is needed.⁹³

Whole-Food, Plant-Based Diet

A whole-food, plant-based (WFPB) diet is another popular dietary approach that consists of eating fruits, vegetables, legumes, nuts, seeds, and grains in their whole natural form.⁹⁴ This diet discourages all animal products, including red meat, seafood, dairy, and eggs. It is similar to a vegan diet except that it eliminates all highly refined carbohydrates, vegetable oils, and other processed foods.⁹⁴ Randomized clinical studies have demonstrated the WFPB diet to be effective in the treatment of obesity and metabolic syndrome.^95,96

A WFPB diet has been shown to increase the antioxidant capacity of cells, lengthen telomeres, and reduce formation of advanced glycation end products.^94,97,98 These benefits may help combat accelerated skin aging, including increased skin permeability, reduced elasticity and hydration, decreased angiogenesis, impaired immune function, and decreased vitamin D synthesis. Accelerated skin aging can result in delayed wound healing and susceptibility to skin tears and ecchymoses and also may promote the development of cutaneous malignancies.⁹⁹ There remains a lack of clinical data studying a properly formulated WFPB diet in the dermatologic setting.

Paleolithic Diet

The paleolithic (Paleo) diet is an increasingly popular way of eating that attempts to mirror what our ancestors may have consumed between 10,000 and 2.5 million years ago.¹⁰⁰ It is similar to the Mediterranean diet but excludes grains, dairy, legumes, and nightshade vegetables. It also calls for elimination of highly processed sugars and oils as well as chemical food additives and preservatives. There is a strict variation of the diet for individuals with autoimmune disease that also excludes eggs, nuts, and seeds, as these can be inflammatory or immunogenic in some patients.^100-106 Other variations of the diet exist, including the ketogenic Paleo diet, pegan (Paleo vegan) diet, and lacto-Paleo diet.¹⁰⁰ An often cited criticism of the Paleo diet is the low intake of calcium and risk for osteoporosis; however, consumption of calcium-rich foods or a calcium supplement can address this concern.¹⁰⁷

Although small clinical studies have found the Paleo diet to be beneficial for various autoimmune diseases, clinical data evaluating the utility of the diet for cutaneous disease is lacking.^108,109 Numerous randomized trials have demonstrated the Paleo diet to be effective for weight loss and improving insulin sensitivity and lipid levels.^110-116 Thus, the Paleo diet may theoretically serve as a viable adjunct dietary approach to the treatment of cutaneous diseases associated with obesity and metabolic derangement.¹¹⁷

Carnivore Diet

Arguably the most controversial and radical diet is the carnivore diet. As the name implies, the carnivore diet is based on consuming solely animal products. A properly structured carnivore diet emphasizes a “nose-to-tail” eating approach where all parts of the animal including the muscle meats, organs, and fat are consumed. Proponents of the diet cite anthropologic evidence from fossil-stable carbon-13/carbon-12 isotope analyses, craniodental features, and numerous other adaptations that indicate increased consumption of meat during human evolution.^118-122 Notably, many early humans ate a carnivore diet, but life span was very short at this time, suggesting the diet may not be as beneficial as has been suggested.

Despite the abundance of anecdotal evidence supporting its use for a variety of chronic conditions, including cutaneous autoimmune disease, there is a virtual absence of high-quality research on the carnivore diet.^123-125

The purported benefits of the carnivore diet may be attributed to the consumption of organ meats that contain highly bioavailable essential vitamins and minerals, such as iron, zinc, copper, selenium, thiamine, niacin, folate, vitamin B₆, vitamin B₁₂, vitamin A, vitamin D, vitamin K, and choline.^126-128 Other dietary compounds that have demonstrated benefit for skin health and are predominantly found in animal foods include carnosine, carnitine, creatine, taurine, coenzyme Q10, and collagen.^129-134 Nevertheless, there is no data to recommend the elimination of antioxidant- and micronutrient-dense plant-based foods. Rigorous clinical research evaluating the efficacy and safety of the carnivore diet in dermatologic patients is needed. A carnivore diet should not be undertaken without the assistance of a dietician who can ensure adequate micronutrient and macronutrient support.

Final Thoughts

The adjunctive role of diet in the treatment of skin disease is expanding and becoming more widely accepted among dermatologists. Unfortunately, there remains a lack of randomized controlled trials confirming the efficacy of various dietary interventions in the dermatologic setting. Although evidence-based dietary recommendations currently are limited, it is important for dermatologists to be aware of the varied and nuanced dietary interventions employed by patients.

Ultimately, dietary recommendations must be personalized, considering a patient’s comorbidities, personal beliefs and preferences, and nutrigenetics. The emerging field of dermatonutrigenomics—the study of how dietary compounds interact with one’s genes to influence skin health—may allow for precise dietary recommendations to be made in dermatologic practice. Direct-to-consumer genetic tests targeted toward dermatology patients are already on the market, but their clinical utility awaits validation.¹ Because nutritional science is a constantly evolving field, becoming familiar with these popular diets will serve both dermatologists and their patients well.

Within the last decade, almost 3000 articles have been published on the role of diet in the prevention and management of dermatologic conditions. Patients are increasingly interested in—and employing—dietary modifications that may influence skin appearance and aid in the treatment of cutaneous disease.¹ It is essential that dermatologists are familiar with existing evidence on the role of diet in dermatology to counsel patients appropriately. Herein, we discuss the compositions of several popular diets and their proposed utility for dermatologic purposes. We highlight the limited literature that exists surrounding this topic and emphasize the need for future, well-designed clinical trials that study the impact of diet on skin disease.

Ketogenic Diet

The ketogenic diet has a macronutrient profile composed of high fat, low to moderate protein, and very low carbohydrates. Nutritional ketosis occurs as the body begins to use free fatty acids (via beta oxidation) as the primary metabolite driving cellular metabolism. It has been suggested that the ketogenic diet may impart beneficial effects on skin disease; however, limited literature exists on the role of nutritional ketosis in the treatment of dermatologic conditions.

Mechanistically, the ketogenic diet decreases the secretion of insulin and insulinlike growth factor 1, resulting in a reduction of circulating androgens and increased activity of the retinoid X receptor.² In acne vulgaris, it has been suggested that the ketogenic diet may be beneficial in decreasing androgen-induced sebum production and the overproliferation of keratinocytes.^2-7 The ketogenic diet is one of the most rapidly effective dietary strategies for normalizing both insulin and androgens, thus it may theoretically be useful for other metabolic and hormone-dependent skin diseases, such as hidradenitis suppurativa.^8,9

The cutaneous manifestations associated with chronic hyperinsulinemia and hyperglycemia are numerous and include acanthosis nigricans, acrochordons, diabetic dermopathy, scleredema diabeticorum, bullosis diabeticorum, keratosis pilaris, and generalized granuloma annulare. There also is an increased risk for bacterial and fungal skin infections associated with hyperglycemic states.¹⁰ The ketogenic diet is an effective nonpharmacologic tool for normalizing serum insulin and glucose levels in most patients and may have utility in the aforementioned conditions.^11,12 In addition to improving insulin sensitivity, it has been used as a dietary strategy for weight loss.^11-15 Because obesity and metabolic syndrome are highly correlated with common skin conditions such as psoriasis, hidradenitis suppurativa, and androgenetic alopecia, there may be a role for employing the ketogenic diet in these patient populations.^16,17

Although robust clinical studies on ketogenic diets in skin disease are lacking, a recent single-arm, open-label clinical trial observed benefit in all 37 drug-naïve, overweight patients with chronic plaque psoriasis who underwent a ketogenic weight loss protocol. Significant reductions in psoriasis area and severity index (PASI) score and dermatology life quality index score were reported (P<.001).¹⁸ Another study of 30 patients with psoriasis found that a 4-week, low-calorie, ketogenic diet resulted in 50% improvement of PASI scores, 10% weight loss, and a reduction in the proinflammatory cytokines IL-1β and IL-2.¹⁹ Despite these results, it is a challenge to tease out if the specific dietary intervention or its associated weight loss was the main driver in these reported improvements in skin disease.

There is mixed evidence on the anti-inflammatory nature of the ketogenic diet, likely due to wide variation in the composition of foods included in individual diets. In many instances, the ketogenic diet is thought to possess considerable antioxidant and anti-inflammatory capabilities. Ketones are known activators of the nuclear factor erythroid 2–related factor 2 pathway, which upregulates the production of glutathione, a major endogenous intracellular antioxidant.²⁰ Additionally, dietary compounds from foods that are encouraged while on the ketogenic diet, such as sulforaphane from broccoli, also are independent activators of nuclear factor erythroid 2–related factor 2.²¹ Ketones are efficiently utilized by mitochondria, which also may result in the decreased production of reactive oxygen species and lower oxidative stress.²² Moreover, the ketone body β-hydroxybutyrate has demonstrated the ability to reduce proinflammatory IL-1β levels via suppression of nucleotide-binding domain-like receptor protein 3 inflammasome activity.^23,24 The activity of IL-1β is known to be elevated in many dermatologic conditions, including juvenile idiopathic arthritis, relapsing polychondritis, Schnitzler syndrome, hidradenitis suppurativa, Behçet disease, and other autoinflammatory syndromes.²⁵ Ketones also have been shown to inhibit the nuclear factor–κB proinflammatory signaling pathway.^22,26,27 Overexpression of IL-1β and aberrant activation of nuclear factor–κB are implicated in a variety of inflammatory, autoimmune, and oncologic cutaneous pathologies. The ketogenic diet may prove to be an effective adjunctive treatment for dermatologists to consider in select patient populations.^23,24,28-30

For patients with keratinocyte carcinomas, the ketogenic diet may offer the aforementioned anti-inflammatory and antioxidant effects, as well as suppression of the mechanistic target of rapamycin, a major regulator of cell metabolism and proliferation.^31,32 Inhibition of mechanistic target of rapamycin activity has been shown to slow tumor growth and reduce the development of squamous cell carcinoma.^25,33,34 The ketogenic diet also may exploit the preferential utilization of glucose exhibited by many types of cancer cells, thereby “starving” the tumor of its primary fuel source.^35,36 In vitro and animal studies in a variety of cancer types have demonstrated that a ketogenic metabolic state—achieved through the ketogenic diet or fasting—can sensitize tumor cells to chemotherapy and radiation while conferring a protective effect to normal cells.^37-40 This recently described phenomenon is known as differential stress resistance, but it has not been studied in keratinocyte malignancies or melanoma to date. Importantly, some basal cell carcinomas and BRAF V600E–mutated melanomas have worsened while on the ketogenic diet, suggesting more data is needed before it can be recommended for all cancer patients.^41,42 Furthermore, other skin conditions such as prurigo pigmentosa have been associated with initiation of the ketogenic diet.⁴³

Low FODMAP Diet

Fermentable oligosaccharides, disaccharides, monosaccharides, and polyols (FODMAPs) are short-chain carbohydrates that are poorly absorbed, osmotically active, and rapidly fermented by intestinal bacteria.⁴⁴ The low FODMAP diet has been shown to be efficacious for treatment of irritable bowel syndrome, small intestinal bacterial overgrowth (SIBO), and some cases of inflammatory bowel disease (IBD).^44-49 A low FODMAP diet may have potential implications for several dermatologic conditions.

Rosacea has been associated with various gastrointestinal tract disorders including irritable bowel syndrome, SIBO, and IBD.^50-54 A single study found that patients with rosacea had a 13-fold increased risk for SIBO.^55,56 Treatment of 40 patients with SIBO using rifaximin resulted in complete resolution of rosacea in all patients, with no relapse after a 3-year follow-up period.⁵⁵ Psoriasis also has been associated with SIBO and IBD.^57,58 One small study found that eradication of SIBO in psoriatic patients resulted in improved PASI scores and colorimetric values.⁵⁹

Although the long-term health consequences of the low FODMAP diet are unknown, further research on such dietary interventions for inflammatory skin conditions is warranted given the mounting evidence of a gut-skin connection and the role of the intestinal microbiome in skin health.^50,51

Gluten-Free Diet

Gluten is a protein found in a variety of grains. Although the role of gluten in the pathogenesis of celiac disease and dermatitis herpetiformis is indisputable, the deleterious effects of gluten outside of the context of these diseases remain controversial. There may be a compelling case for eliminating gluten in psoriasis patients with seropositivity for celiac disease. A recent systematic review found a 2.2-fold increased risk for celiac disease in psoriasis patients.⁶⁰ Antigliadin antibody titers also were found to be positively correlated with psoriatic disease severity.⁶¹ In addition, one open-label study found a reduction in PASI scores in 73% of patients with antigliadin antibodies after 3 months on a gluten-free diet compared to those without antibodies; however, the study only included 22 patients.⁶² Several other small studies have yielded similar results^63,64; however, antigliadin antibodies are neither the most sensitive nor specific markers of celiac disease, and additional testing should be completed in any patient who may carry this diagnosis. A survey study by the National Psoriasis Foundation found that the dietary change associated with the greatest skin improvement was removal of gluten and nightshade vegetables in approximately 50% of the 1200 psoriasis patients that responded.⁶⁵ Case reports of various dermatologic conditions including sarcoidosis, vitiligo, alopecia areata, lichen planus, dermatomyositis, pyoderma gangrenosum, erythema nodosum, leukocytoclastic vasculitis, linear IgA bullous dermatosis, and aphthous ulcerations have reportedly improved with a gluten-free diet; however, this should not be used as primary therapy in patients without celiac disease.^66-71 Because gluten-free diets can be expensive and challenging to follow, a formal assessment for celiac disease should be considered before recommendation of this dietary intervention.

Low Histamine Diet

Histamine is a biogenic amine produced by the decarboxylation of the amino acid histidine.⁷² It is found in several foods in varying amounts. Because bacteria can convert histidine into histamine, many fermented and aged foods such as kimchi, sauerkraut, cheese, and red wine contain high levels of histamine. Individuals who have decreased activity of diamine oxidase (DAO), an enzyme that degrades histamine, may be more susceptible to histamine intolerance.⁷² The symptoms of histamine intolerance are numerous and include gastrointestinal tract distress, rhinorrhea and nasal congestion, headache, urticaria, flushing, and pruritus. Histamine intolerance can mimic an IgE-mediated food allergy; however, allergy testing is negative in these patients. Unfortunately, there is no laboratory test for histamine intolerance; a double-blind, placebo-controlled food challenge is considered the gold-standard test.⁷²

As it pertains to dermatology, a low histamine diet may play a role in the treatment of certain patients with atopic dermatitis and chronic spontaneous urticaria. One study reported that 17 of 54 (31.5%) atopic patients had higher basal levels of serum histamine compared to controls.⁷³ Another study found that a histamine-free diet led to improvement in both histamine intolerance symptoms and atopic dermatitis disease severity (SCORing atopic dermatitis) in patients with low DAO activity.⁷⁴ In chronic spontaneous urticaria, a recent systematic review found that in 223 patients placed on a low histamine diet for 3 to 4 weeks, 12% and 44% achieved complete and partial remission, respectively.⁷⁵ Although treatment response based on a patient’s DAO activity level has not been correlated, a diet low in histamine may prove useful for patients with persistent atopic dermatitis and chronic spontaneous urticaria who have negative food allergy tests and report exacerbation of symptoms after ingestion of histamine-rich foods.^76,77

Mediterranean Diet

The Mediterranean diet has been touted as one of the healthiest diets to date, and large randomized clinical trials have demonstrated its effectiveness in weight loss, improving insulin sensitivity, and reducing inflammatory cytokine profiles.^78,79 A major criticism of the Mediterranean diet is that it has considerable ambiguity and lacks a precise definition due to the variability of what is consumed in different Mediterranean regions. Generally, the diet emphasizes high consumption of colorful fruits and vegetables, aromatic herbs and spices, olive oil, nuts, and seafood, as well as modest amounts of dairy, eggs, and red meat.⁸⁰ The anti-inflammatory effects of this diet largely have been attributed to its abundance of polyphenols, carotenoids, monounsaturated fatty acids, and omega-3 polyunsaturated fatty acids (PUFAs).^80,81 Examples of polyphenols include resveratrol in red grapes, quercetin in apples and red onions, and curcumin in turmeric, while examples of carotenoids include lycopene in tomatoes and zeaxanthin in dark leafy greens. Oleic acid is a monounsaturated fatty acid present in high concentrations in olive oil, while eicosapentaenoic acid and docosahexaenoic acid are omega-3 PUFAs predominantly found in fish.⁸²

Unfortunately, rigorous clinical trials regarding the Mediterranean diet as it pertains to dermatology have not been undertaken. Numerous observational studies in patients with psoriasis have suggested that close adherence to the Mediterranean diet was associated with improvement in PASI scores.^83-86 The National Psoriasis Foundation now recommends a trial of the Mediterranean diet in some patients with psoriasis, emphasizing increased dietary intake of olive oil, fish, and vegetables.⁸⁷ Adherence to a Mediterranean diet also has been inversely correlated to the severity of acne vulgaris and hidradenitis suppurativa^88,89; however, these studies failed to account for the multifactorial risk factors associated with these conditions. Mediterranean diets also may impart a chemopreventive effect, supported by a number of in vivo and in vitro studies demonstrating the inhibition and/or reversal of cutaneous DNA damage induced by UV radiation through supplementation with various phytonutrients and omega-3 PUFAs.^81,90-92 Although small case-control studies have found a decreased risk of basal cell carcinoma in those who closely adhered to a Mediterranean diet, more rigorous clinical research is needed.⁹³

Whole-Food, Plant-Based Diet

A whole-food, plant-based (WFPB) diet is another popular dietary approach that consists of eating fruits, vegetables, legumes, nuts, seeds, and grains in their whole natural form.⁹⁴ This diet discourages all animal products, including red meat, seafood, dairy, and eggs. It is similar to a vegan diet except that it eliminates all highly refined carbohydrates, vegetable oils, and other processed foods.⁹⁴ Randomized clinical studies have demonstrated the WFPB diet to be effective in the treatment of obesity and metabolic syndrome.^95,96

A WFPB diet has been shown to increase the antioxidant capacity of cells, lengthen telomeres, and reduce formation of advanced glycation end products.^94,97,98 These benefits may help combat accelerated skin aging, including increased skin permeability, reduced elasticity and hydration, decreased angiogenesis, impaired immune function, and decreased vitamin D synthesis. Accelerated skin aging can result in delayed wound healing and susceptibility to skin tears and ecchymoses and also may promote the development of cutaneous malignancies.⁹⁹ There remains a lack of clinical data studying a properly formulated WFPB diet in the dermatologic setting.

Paleolithic Diet

The paleolithic (Paleo) diet is an increasingly popular way of eating that attempts to mirror what our ancestors may have consumed between 10,000 and 2.5 million years ago.¹⁰⁰ It is similar to the Mediterranean diet but excludes grains, dairy, legumes, and nightshade vegetables. It also calls for elimination of highly processed sugars and oils as well as chemical food additives and preservatives. There is a strict variation of the diet for individuals with autoimmune disease that also excludes eggs, nuts, and seeds, as these can be inflammatory or immunogenic in some patients.^100-106 Other variations of the diet exist, including the ketogenic Paleo diet, pegan (Paleo vegan) diet, and lacto-Paleo diet.¹⁰⁰ An often cited criticism of the Paleo diet is the low intake of calcium and risk for osteoporosis; however, consumption of calcium-rich foods or a calcium supplement can address this concern.¹⁰⁷

Although small clinical studies have found the Paleo diet to be beneficial for various autoimmune diseases, clinical data evaluating the utility of the diet for cutaneous disease is lacking.^108,109 Numerous randomized trials have demonstrated the Paleo diet to be effective for weight loss and improving insulin sensitivity and lipid levels.^110-116 Thus, the Paleo diet may theoretically serve as a viable adjunct dietary approach to the treatment of cutaneous diseases associated with obesity and metabolic derangement.¹¹⁷

Carnivore Diet

Arguably the most controversial and radical diet is the carnivore diet. As the name implies, the carnivore diet is based on consuming solely animal products. A properly structured carnivore diet emphasizes a “nose-to-tail” eating approach where all parts of the animal including the muscle meats, organs, and fat are consumed. Proponents of the diet cite anthropologic evidence from fossil-stable carbon-13/carbon-12 isotope analyses, craniodental features, and numerous other adaptations that indicate increased consumption of meat during human evolution.^118-122 Notably, many early humans ate a carnivore diet, but life span was very short at this time, suggesting the diet may not be as beneficial as has been suggested.

Despite the abundance of anecdotal evidence supporting its use for a variety of chronic conditions, including cutaneous autoimmune disease, there is a virtual absence of high-quality research on the carnivore diet.^123-125

The purported benefits of the carnivore diet may be attributed to the consumption of organ meats that contain highly bioavailable essential vitamins and minerals, such as iron, zinc, copper, selenium, thiamine, niacin, folate, vitamin B₆, vitamin B₁₂, vitamin A, vitamin D, vitamin K, and choline.^126-128 Other dietary compounds that have demonstrated benefit for skin health and are predominantly found in animal foods include carnosine, carnitine, creatine, taurine, coenzyme Q10, and collagen.^129-134 Nevertheless, there is no data to recommend the elimination of antioxidant- and micronutrient-dense plant-based foods. Rigorous clinical research evaluating the efficacy and safety of the carnivore diet in dermatologic patients is needed. A carnivore diet should not be undertaken without the assistance of a dietician who can ensure adequate micronutrient and macronutrient support.

Final Thoughts

The adjunctive role of diet in the treatment of skin disease is expanding and becoming more widely accepted among dermatologists. Unfortunately, there remains a lack of randomized controlled trials confirming the efficacy of various dietary interventions in the dermatologic setting. Although evidence-based dietary recommendations currently are limited, it is important for dermatologists to be aware of the varied and nuanced dietary interventions employed by patients.

Ultimately, dietary recommendations must be personalized, considering a patient’s comorbidities, personal beliefs and preferences, and nutrigenetics. The emerging field of dermatonutrigenomics—the study of how dietary compounds interact with one’s genes to influence skin health—may allow for precise dietary recommendations to be made in dermatologic practice. Direct-to-consumer genetic tests targeted toward dermatology patients are already on the market, but their clinical utility awaits validation.¹ Because nutritional science is a constantly evolving field, becoming familiar with these popular diets will serve both dermatologists and their patients well.

Multidisciplinary tumor boards are composed of providers from many fields who deliver coordinated care for patients with unresectable and high-risk skin cancers. Providers who comprise the tumor board often are radiation oncologists, hematologists/oncologists, general surgeons, dermatologists, dermatologic surgeons, and pathologists. The benefit of having a tumor board is that each patient is evaluated simultaneously by a group of physicians from various specialties who bring diverse perspectives that will contribute to the overall treatment plan. The cases often encompass high-risk tumors including unresectable basal cell carcinomas or invasive melanomas. By combining knowledge from each specialty in a team approach, the tumor board can effectively and holistically develop a care plan for each patient.

For the tumor board at the Warren Alpert Medical School of Brown University (Providence, Rhode Island), we often prepare a presentation with comprehensive details about the patient and tumor. During the presentation, we also propose a treatment plan prior to describing each patient at the weekly conference and amend the plans during the discussion. Tumor boards also provide a consulting role to the community and hospital providers in which patients are being referred by their primary provider and are seeking a second opinion or guidance.

In many ways, the tumor board is a multidisciplinary approach for patient advocacy in the form of treatment. These physicians meet on a regular basis to check on the patient’s progress and continually reevaluate how to have discussions about the patient’s care. There are many reasons why it is important to refer patients to a multidisciplinary tumor board.

Improved Workup and Diagnosis

One of the values of a tumor board is that it allows for patient data to be collected and assembled in a way that tells a story. The specialist from each field can then discuss and weigh the benefits and risks for each diagnostic test that should be performed for the workup in each patient. Physicians who refer their patients to the tumor board use their recommendations to both confirm the diagnosis and shift their treatment plans, depending on the information presented during the meeting.¹ There may be a change in the tumor type, decision to refer for surgery, cancer staging, and list of viable options, especially after reviewing pathology and imaging.² The discussion of the treatment plan may consider not only surgical considerations but also the patient’s quality of life. At times, noninvasive interventions are more appropriate and align with the patient’s goals of care. In addition, during the tumor board clinic there may be new tumors that are identified and biopsied, providing increased diagnosis and surveillance for patients who may have a higher risk for developing skin cancer.

Education for Residents and Providers

The multidisciplinary tumor board not only helps patients but also educates both residents and providers on the evidence-based therapeutic management of high-risk tumors.² Research literature on cutaneous oncology is dynamic, and the weekly tumor board meetings help providers stay informed about the best and most effective treatments for their patients.³ In addition to the attending specialists, participants of the tumor board also may include residents, medical students, medical assistance staff, nurses, physician assistants, and fellows. Furthermore, the recommendations given by the tumor board serve to educate both the patient and the provider who referred them to the tumor board. Although we have access to excellent dermatology textbooks as residents, the most impactful educational experience is seeing the patients in tumor board clinic and participating in the immensely educational discussions at the weekly conferences. Through this experience, I have learned that treatment plans should be personalized to the patient. There are many factors to take into consideration when deciphering what the best course of treatment will be for a patient. Sometimes the best option is Mohs micrographic surgery, while other times it may be scheduling several sessions of palliative radiation oncology. Treatment depends on the individual patient and their condition.

Coordination of Care

During a week that I was on call, I was consulted to biopsy a patient with a giant hemorrhagic basal cell carcinoma that caused substantial cheek and nose distortion as well as anemia secondary to acute blood loss. The patient not only did not have a dermatologist but also did not have a primary care physician given he had not had contact with the health care system in more than 30 years. The reason for him not seeking care was multifactorial, but the approach to his care became multidisciplinary. We sought to connect him with the right providers to help him in any way that we could. We presented him at our multidisciplinary tumor board and started him on sonedigib, a medication that binds to and inhibits the smoothened protein.⁴ Through the tumor board, we were able to establish sustained contact with the patient. The tumor board created effective communication between providers to get him the referrals that he needed for dermatology, pathology, radiation oncology, hematology/oncology, and otolaryngology. The discussions centered around being cognizant of the patient’s apprehension with the health care system as well as providing medical and surgical treatment that would help his quality of life. We built a consensus on what the best plan was for the patient and his family. This consensus would have been more difficult had it not been for the combined specialties of the tumor board. In general, studies have shown that weekly tumor boards have resulted in decreased mortality rates for patients with advanced cancers.⁵

Final Thoughts

The multidisciplinary tumor board is a powerful resource for hospitals and the greater medical community. At these weekly conferences you realize there may still be hope that begins at the line where your expertise ends. It represents a team of providers who compassionately refuse to give up on patients when they are the last refuge.

Multidisciplinary tumor boards are composed of providers from many fields who deliver coordinated care for patients with unresectable and high-risk skin cancers. Providers who comprise the tumor board often are radiation oncologists, hematologists/oncologists, general surgeons, dermatologists, dermatologic surgeons, and pathologists. The benefit of having a tumor board is that each patient is evaluated simultaneously by a group of physicians from various specialties who bring diverse perspectives that will contribute to the overall treatment plan. The cases often encompass high-risk tumors including unresectable basal cell carcinomas or invasive melanomas. By combining knowledge from each specialty in a team approach, the tumor board can effectively and holistically develop a care plan for each patient.

For the tumor board at the Warren Alpert Medical School of Brown University (Providence, Rhode Island), we often prepare a presentation with comprehensive details about the patient and tumor. During the presentation, we also propose a treatment plan prior to describing each patient at the weekly conference and amend the plans during the discussion. Tumor boards also provide a consulting role to the community and hospital providers in which patients are being referred by their primary provider and are seeking a second opinion or guidance.

In many ways, the tumor board is a multidisciplinary approach for patient advocacy in the form of treatment. These physicians meet on a regular basis to check on the patient’s progress and continually reevaluate how to have discussions about the patient’s care. There are many reasons why it is important to refer patients to a multidisciplinary tumor board.

Improved Workup and Diagnosis

One of the values of a tumor board is that it allows for patient data to be collected and assembled in a way that tells a story. The specialist from each field can then discuss and weigh the benefits and risks for each diagnostic test that should be performed for the workup in each patient. Physicians who refer their patients to the tumor board use their recommendations to both confirm the diagnosis and shift their treatment plans, depending on the information presented during the meeting.¹ There may be a change in the tumor type, decision to refer for surgery, cancer staging, and list of viable options, especially after reviewing pathology and imaging.² The discussion of the treatment plan may consider not only surgical considerations but also the patient’s quality of life. At times, noninvasive interventions are more appropriate and align with the patient’s goals of care. In addition, during the tumor board clinic there may be new tumors that are identified and biopsied, providing increased diagnosis and surveillance for patients who may have a higher risk for developing skin cancer.

Education for Residents and Providers

The multidisciplinary tumor board not only helps patients but also educates both residents and providers on the evidence-based therapeutic management of high-risk tumors.² Research literature on cutaneous oncology is dynamic, and the weekly tumor board meetings help providers stay informed about the best and most effective treatments for their patients.³ In addition to the attending specialists, participants of the tumor board also may include residents, medical students, medical assistance staff, nurses, physician assistants, and fellows. Furthermore, the recommendations given by the tumor board serve to educate both the patient and the provider who referred them to the tumor board. Although we have access to excellent dermatology textbooks as residents, the most impactful educational experience is seeing the patients in tumor board clinic and participating in the immensely educational discussions at the weekly conferences. Through this experience, I have learned that treatment plans should be personalized to the patient. There are many factors to take into consideration when deciphering what the best course of treatment will be for a patient. Sometimes the best option is Mohs micrographic surgery, while other times it may be scheduling several sessions of palliative radiation oncology. Treatment depends on the individual patient and their condition.

Coordination of Care

During a week that I was on call, I was consulted to biopsy a patient with a giant hemorrhagic basal cell carcinoma that caused substantial cheek and nose distortion as well as anemia secondary to acute blood loss. The patient not only did not have a dermatologist but also did not have a primary care physician given he had not had contact with the health care system in more than 30 years. The reason for him not seeking care was multifactorial, but the approach to his care became multidisciplinary. We sought to connect him with the right providers to help him in any way that we could. We presented him at our multidisciplinary tumor board and started him on sonedigib, a medication that binds to and inhibits the smoothened protein.⁴ Through the tumor board, we were able to establish sustained contact with the patient. The tumor board created effective communication between providers to get him the referrals that he needed for dermatology, pathology, radiation oncology, hematology/oncology, and otolaryngology. The discussions centered around being cognizant of the patient’s apprehension with the health care system as well as providing medical and surgical treatment that would help his quality of life. We built a consensus on what the best plan was for the patient and his family. This consensus would have been more difficult had it not been for the combined specialties of the tumor board. In general, studies have shown that weekly tumor boards have resulted in decreased mortality rates for patients with advanced cancers.⁵

Final Thoughts

The multidisciplinary tumor board is a powerful resource for hospitals and the greater medical community. At these weekly conferences you realize there may still be hope that begins at the line where your expertise ends. It represents a team of providers who compassionately refuse to give up on patients when they are the last refuge.

Multidisciplinary tumor boards are composed of providers from many fields who deliver coordinated care for patients with unresectable and high-risk skin cancers. Providers who comprise the tumor board often are radiation oncologists, hematologists/oncologists, general surgeons, dermatologists, dermatologic surgeons, and pathologists. The benefit of having a tumor board is that each patient is evaluated simultaneously by a group of physicians from various specialties who bring diverse perspectives that will contribute to the overall treatment plan. The cases often encompass high-risk tumors including unresectable basal cell carcinomas or invasive melanomas. By combining knowledge from each specialty in a team approach, the tumor board can effectively and holistically develop a care plan for each patient.

For the tumor board at the Warren Alpert Medical School of Brown University (Providence, Rhode Island), we often prepare a presentation with comprehensive details about the patient and tumor. During the presentation, we also propose a treatment plan prior to describing each patient at the weekly conference and amend the plans during the discussion. Tumor boards also provide a consulting role to the community and hospital providers in which patients are being referred by their primary provider and are seeking a second opinion or guidance.

In many ways, the tumor board is a multidisciplinary approach for patient advocacy in the form of treatment. These physicians meet on a regular basis to check on the patient’s progress and continually reevaluate how to have discussions about the patient’s care. There are many reasons why it is important to refer patients to a multidisciplinary tumor board.

Improved Workup and Diagnosis

One of the values of a tumor board is that it allows for patient data to be collected and assembled in a way that tells a story. The specialist from each field can then discuss and weigh the benefits and risks for each diagnostic test that should be performed for the workup in each patient. Physicians who refer their patients to the tumor board use their recommendations to both confirm the diagnosis and shift their treatment plans, depending on the information presented during the meeting.¹ There may be a change in the tumor type, decision to refer for surgery, cancer staging, and list of viable options, especially after reviewing pathology and imaging.² The discussion of the treatment plan may consider not only surgical considerations but also the patient’s quality of life. At times, noninvasive interventions are more appropriate and align with the patient’s goals of care. In addition, during the tumor board clinic there may be new tumors that are identified and biopsied, providing increased diagnosis and surveillance for patients who may have a higher risk for developing skin cancer.

Education for Residents and Providers

The multidisciplinary tumor board not only helps patients but also educates both residents and providers on the evidence-based therapeutic management of high-risk tumors.² Research literature on cutaneous oncology is dynamic, and the weekly tumor board meetings help providers stay informed about the best and most effective treatments for their patients.³ In addition to the attending specialists, participants of the tumor board also may include residents, medical students, medical assistance staff, nurses, physician assistants, and fellows. Furthermore, the recommendations given by the tumor board serve to educate both the patient and the provider who referred them to the tumor board. Although we have access to excellent dermatology textbooks as residents, the most impactful educational experience is seeing the patients in tumor board clinic and participating in the immensely educational discussions at the weekly conferences. Through this experience, I have learned that treatment plans should be personalized to the patient. There are many factors to take into consideration when deciphering what the best course of treatment will be for a patient. Sometimes the best option is Mohs micrographic surgery, while other times it may be scheduling several sessions of palliative radiation oncology. Treatment depends on the individual patient and their condition.

Coordination of Care

During a week that I was on call, I was consulted to biopsy a patient with a giant hemorrhagic basal cell carcinoma that caused substantial cheek and nose distortion as well as anemia secondary to acute blood loss. The patient not only did not have a dermatologist but also did not have a primary care physician given he had not had contact with the health care system in more than 30 years. The reason for him not seeking care was multifactorial, but the approach to his care became multidisciplinary. We sought to connect him with the right providers to help him in any way that we could. We presented him at our multidisciplinary tumor board and started him on sonedigib, a medication that binds to and inhibits the smoothened protein.⁴ Through the tumor board, we were able to establish sustained contact with the patient. The tumor board created effective communication between providers to get him the referrals that he needed for dermatology, pathology, radiation oncology, hematology/oncology, and otolaryngology. The discussions centered around being cognizant of the patient’s apprehension with the health care system as well as providing medical and surgical treatment that would help his quality of life. We built a consensus on what the best plan was for the patient and his family. This consensus would have been more difficult had it not been for the combined specialties of the tumor board. In general, studies have shown that weekly tumor boards have resulted in decreased mortality rates for patients with advanced cancers.⁵

Final Thoughts

The multidisciplinary tumor board is a powerful resource for hospitals and the greater medical community. At these weekly conferences you realize there may still be hope that begins at the line where your expertise ends. It represents a team of providers who compassionately refuse to give up on patients when they are the last refuge.

There were no local recurrences when Mohs surgery was used to treat early stage Merkel cell carcinomas in 53 patients at the Zitelli and Brodland Skin Cancer Center, Pittsburgh.

The results compare favorably with the standard treatment approach, wide local excision with or without radiation, which has a local recurrence rate of 4.2%-31.7% because of incomplete excision or false negative margins, said Vitaly Terushkin, MD, a Mohs surgeon who presented the findings of the study, a retrospective chart review, at the annual meeting of the American College of Mohs Surgery.

Mohs surgery as monotherapy offered “survival at least as good as historical controls treated with wide local excision plus radiation therapy, and because of the superior local control, Mohs surgery may obviate the need for adjuvant radiation and decrease the chance for additional surgery for the treatment of local recurrence,” said Dr. Terushkin, now in practice in the New York City area.

“We hope this data fuel additional studies with larger cohorts to continue to explore the value of Mohs for Merkel cell carcinoma,” he said.

The findings add to a growing body of literature supporting Mohs for many types of rare tumors. “Micrographic surgery or complete circumferential peripheral and deep margin analysis has been shown to be superior to wide local excision in a variety of tumors and clinical scenarios,” said Vishal Patel, MD, assistant professor of dermatology and director of the cutaneous oncology program at George Washington University, Washington.

“When the entire margin is able to be evaluated over random bread-loafed sections, there is growing evidence that this leads to superior outcomes and disease specific mortality,” he said when asked for comment on the study results.

In all, 56 primary Merkel cell carcinomas were treated in the 53 patients from 2001 to 2019; about two-thirds of the patients had stage 1 tumors and the rest stage 2a.

They were treated with Mohs alone, without radiation. Average follow up was 4.6 years, with about a third of patients followed for 5 or more years.

The average age of the patients was 78 years, and just over half were men. In more than half the cases, tumors were located on the head and neck (62.5%), and the mean tumor size was 1.7 cm. Patients were negative for lymphadenopathy and declined lymph node biopsy.

Although there was no local recurrence, defined as tumor reemerging within or adjacent to the surgery site, 7 patients (12.7%) developed in-transit metastases, 13 (23.6%) developed nodal metastases, and 3 developed distant metastases.

The 5-year disease-specific survival rate was 91.2% for stage 1 and 68.6% for stage 2a patients, which compared favorably with historical controls treated with wide local excision with or without radiation, with reported 5-year disease-specific survival rates of 81%-87% for stage 1 disease and 63%-67% for stage 2. Although radiation wasn’t used in the study, Dr. Patel noted that more investigation is needed about the role of adjuvant radiation therapy after Mohs surgery “given recent publications showing improved outcomes in patients with narrow margin excision and postoperative radiation therapy.”

No external funding of the study was reported. Dr. Terushkin had no disclosures. Dr. Patel is a consultant for Sanofi, Regeneron, and Almirall.

[email protected]

There were no local recurrences when Mohs surgery was used to treat early stage Merkel cell carcinomas in 53 patients at the Zitelli and Brodland Skin Cancer Center, Pittsburgh.

The results compare favorably with the standard treatment approach, wide local excision with or without radiation, which has a local recurrence rate of 4.2%-31.7% because of incomplete excision or false negative margins, said Vitaly Terushkin, MD, a Mohs surgeon who presented the findings of the study, a retrospective chart review, at the annual meeting of the American College of Mohs Surgery.

Mohs surgery as monotherapy offered “survival at least as good as historical controls treated with wide local excision plus radiation therapy, and because of the superior local control, Mohs surgery may obviate the need for adjuvant radiation and decrease the chance for additional surgery for the treatment of local recurrence,” said Dr. Terushkin, now in practice in the New York City area.

“We hope this data fuel additional studies with larger cohorts to continue to explore the value of Mohs for Merkel cell carcinoma,” he said.

The findings add to a growing body of literature supporting Mohs for many types of rare tumors. “Micrographic surgery or complete circumferential peripheral and deep margin analysis has been shown to be superior to wide local excision in a variety of tumors and clinical scenarios,” said Vishal Patel, MD, assistant professor of dermatology and director of the cutaneous oncology program at George Washington University, Washington.

“When the entire margin is able to be evaluated over random bread-loafed sections, there is growing evidence that this leads to superior outcomes and disease specific mortality,” he said when asked for comment on the study results.

In all, 56 primary Merkel cell carcinomas were treated in the 53 patients from 2001 to 2019; about two-thirds of the patients had stage 1 tumors and the rest stage 2a.

They were treated with Mohs alone, without radiation. Average follow up was 4.6 years, with about a third of patients followed for 5 or more years.

The average age of the patients was 78 years, and just over half were men. In more than half the cases, tumors were located on the head and neck (62.5%), and the mean tumor size was 1.7 cm. Patients were negative for lymphadenopathy and declined lymph node biopsy.

Although there was no local recurrence, defined as tumor reemerging within or adjacent to the surgery site, 7 patients (12.7%) developed in-transit metastases, 13 (23.6%) developed nodal metastases, and 3 developed distant metastases.

The 5-year disease-specific survival rate was 91.2% for stage 1 and 68.6% for stage 2a patients, which compared favorably with historical controls treated with wide local excision with or without radiation, with reported 5-year disease-specific survival rates of 81%-87% for stage 1 disease and 63%-67% for stage 2. Although radiation wasn’t used in the study, Dr. Patel noted that more investigation is needed about the role of adjuvant radiation therapy after Mohs surgery “given recent publications showing improved outcomes in patients with narrow margin excision and postoperative radiation therapy.”

No external funding of the study was reported. Dr. Terushkin had no disclosures. Dr. Patel is a consultant for Sanofi, Regeneron, and Almirall.

[email protected]

There were no local recurrences when Mohs surgery was used to treat early stage Merkel cell carcinomas in 53 patients at the Zitelli and Brodland Skin Cancer Center, Pittsburgh.

The results compare favorably with the standard treatment approach, wide local excision with or without radiation, which has a local recurrence rate of 4.2%-31.7% because of incomplete excision or false negative margins, said Vitaly Terushkin, MD, a Mohs surgeon who presented the findings of the study, a retrospective chart review, at the annual meeting of the American College of Mohs Surgery.

Mohs surgery as monotherapy offered “survival at least as good as historical controls treated with wide local excision plus radiation therapy, and because of the superior local control, Mohs surgery may obviate the need for adjuvant radiation and decrease the chance for additional surgery for the treatment of local recurrence,” said Dr. Terushkin, now in practice in the New York City area.

“We hope this data fuel additional studies with larger cohorts to continue to explore the value of Mohs for Merkel cell carcinoma,” he said.

The findings add to a growing body of literature supporting Mohs for many types of rare tumors. “Micrographic surgery or complete circumferential peripheral and deep margin analysis has been shown to be superior to wide local excision in a variety of tumors and clinical scenarios,” said Vishal Patel, MD, assistant professor of dermatology and director of the cutaneous oncology program at George Washington University, Washington.

“When the entire margin is able to be evaluated over random bread-loafed sections, there is growing evidence that this leads to superior outcomes and disease specific mortality,” he said when asked for comment on the study results.

In all, 56 primary Merkel cell carcinomas were treated in the 53 patients from 2001 to 2019; about two-thirds of the patients had stage 1 tumors and the rest stage 2a.

They were treated with Mohs alone, without radiation. Average follow up was 4.6 years, with about a third of patients followed for 5 or more years.

The average age of the patients was 78 years, and just over half were men. In more than half the cases, tumors were located on the head and neck (62.5%), and the mean tumor size was 1.7 cm. Patients were negative for lymphadenopathy and declined lymph node biopsy.

Although there was no local recurrence, defined as tumor reemerging within or adjacent to the surgery site, 7 patients (12.7%) developed in-transit metastases, 13 (23.6%) developed nodal metastases, and 3 developed distant metastases.

The 5-year disease-specific survival rate was 91.2% for stage 1 and 68.6% for stage 2a patients, which compared favorably with historical controls treated with wide local excision with or without radiation, with reported 5-year disease-specific survival rates of 81%-87% for stage 1 disease and 63%-67% for stage 2. Although radiation wasn’t used in the study, Dr. Patel noted that more investigation is needed about the role of adjuvant radiation therapy after Mohs surgery “given recent publications showing improved outcomes in patients with narrow margin excision and postoperative radiation therapy.”

No external funding of the study was reported. Dr. Terushkin had no disclosures. Dr. Patel is a consultant for Sanofi, Regeneron, and Almirall.

[email protected]

Valisure, an online pharmacy known for testing every batch of medication it sells, announced that it has petitioned the Food and Drug Administration to recall 40 batches of sunscreens and after-sun products they say tested for high levels of the chemical benzene.

The company tested 294 batches from 69 companies and found benzene in 27% – many in major national brands like Neutrogena and Banana Boat. Some batches contained as much as three times the emergency FDA limit of 2 parts per million.

Long-term exposure to benzene is known to cause cancer in humans.

“This is especially concerning with sunscreen because multiple FDA studies have shown that sunscreen ingredients absorb through the skin and end up in the blood at high levels,” said David Light, CEO of Valisure.

The FDA is seeking more information about the potential risks from common sunscreen ingredients.

“There is not a safe level of benzene that can exist in sunscreen products,” Christopher Bunick, MD, PhD, associate professor of dermatology at Yale University, New Haven, Conn., said in Valisure’s FDA petition. “The total mass of sunscreen required to cover and protect the human body, in single daily application or repeated applications daily, means that even benzene at 0.1 ppm in a sunscreen could expose people to excessively high nanogram amounts of benzene.”

Valisure’s testing previously led to FDA recalls of heartburn medications and hand sanitizers.
 

Examining sunscreen’s environmental impact

Chemicals in sunscreen may be harmful to other forms of life, too. For years, scientists have been examining whether certain chemicals in sunscreen could be causing damage to marine life, in particular the world’s coral reefs. Specific ingredients, including oxybenzone, benzophenone-1, benzophenone-8, OD-PABA, 4-methylbenzylidene camphor, 3-benzylidene camphor, nano-titanium dioxide, nano-zinc oxide, octinoxate, and octocrylene, have been identified as potential risks.

Earlier this year, the National Academies of Sciences, Engineering, and Medicine created a committee to review the existing science about the potential environmental hazards. Over the next 2 years, they’ll also consider the public health implications if people stopped using sunscreen.

Valisure’s announcement included this message: “It is important to note that not all sunscreen products contain benzene and that uncontaminated products are available, should continue to be used, and are important for protecting against potentially harmful solar radiation.”

Using sunscreen with SPF 15 every day can lower risk of squamous cell carcinoma by around 40% and melanoma by 50%. The American Academy of Dermatology recommends a broad-spectrum, water-resistant sunscreen with an SPF of 30 or higher.

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

Valisure, an online pharmacy known for testing every batch of medication it sells, announced that it has petitioned the Food and Drug Administration to recall 40 batches of sunscreens and after-sun products they say tested for high levels of the chemical benzene.

The company tested 294 batches from 69 companies and found benzene in 27% – many in major national brands like Neutrogena and Banana Boat. Some batches contained as much as three times the emergency FDA limit of 2 parts per million.

Long-term exposure to benzene is known to cause cancer in humans.

“This is especially concerning with sunscreen because multiple FDA studies have shown that sunscreen ingredients absorb through the skin and end up in the blood at high levels,” said David Light, CEO of Valisure.

The FDA is seeking more information about the potential risks from common sunscreen ingredients.

“There is not a safe level of benzene that can exist in sunscreen products,” Christopher Bunick, MD, PhD, associate professor of dermatology at Yale University, New Haven, Conn., said in Valisure’s FDA petition. “The total mass of sunscreen required to cover and protect the human body, in single daily application or repeated applications daily, means that even benzene at 0.1 ppm in a sunscreen could expose people to excessively high nanogram amounts of benzene.”

Valisure’s testing previously led to FDA recalls of heartburn medications and hand sanitizers.
 

Examining sunscreen’s environmental impact

Chemicals in sunscreen may be harmful to other forms of life, too. For years, scientists have been examining whether certain chemicals in sunscreen could be causing damage to marine life, in particular the world’s coral reefs. Specific ingredients, including oxybenzone, benzophenone-1, benzophenone-8, OD-PABA, 4-methylbenzylidene camphor, 3-benzylidene camphor, nano-titanium dioxide, nano-zinc oxide, octinoxate, and octocrylene, have been identified as potential risks.

Earlier this year, the National Academies of Sciences, Engineering, and Medicine created a committee to review the existing science about the potential environmental hazards. Over the next 2 years, they’ll also consider the public health implications if people stopped using sunscreen.

Valisure’s announcement included this message: “It is important to note that not all sunscreen products contain benzene and that uncontaminated products are available, should continue to be used, and are important for protecting against potentially harmful solar radiation.”

Using sunscreen with SPF 15 every day can lower risk of squamous cell carcinoma by around 40% and melanoma by 50%. The American Academy of Dermatology recommends a broad-spectrum, water-resistant sunscreen with an SPF of 30 or higher.

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

Valisure, an online pharmacy known for testing every batch of medication it sells, announced that it has petitioned the Food and Drug Administration to recall 40 batches of sunscreens and after-sun products they say tested for high levels of the chemical benzene.

The company tested 294 batches from 69 companies and found benzene in 27% – many in major national brands like Neutrogena and Banana Boat. Some batches contained as much as three times the emergency FDA limit of 2 parts per million.

Long-term exposure to benzene is known to cause cancer in humans.

“This is especially concerning with sunscreen because multiple FDA studies have shown that sunscreen ingredients absorb through the skin and end up in the blood at high levels,” said David Light, CEO of Valisure.

The FDA is seeking more information about the potential risks from common sunscreen ingredients.

“There is not a safe level of benzene that can exist in sunscreen products,” Christopher Bunick, MD, PhD, associate professor of dermatology at Yale University, New Haven, Conn., said in Valisure’s FDA petition. “The total mass of sunscreen required to cover and protect the human body, in single daily application or repeated applications daily, means that even benzene at 0.1 ppm in a sunscreen could expose people to excessively high nanogram amounts of benzene.”

Valisure’s testing previously led to FDA recalls of heartburn medications and hand sanitizers.
 

Examining sunscreen’s environmental impact

Chemicals in sunscreen may be harmful to other forms of life, too. For years, scientists have been examining whether certain chemicals in sunscreen could be causing damage to marine life, in particular the world’s coral reefs. Specific ingredients, including oxybenzone, benzophenone-1, benzophenone-8, OD-PABA, 4-methylbenzylidene camphor, 3-benzylidene camphor, nano-titanium dioxide, nano-zinc oxide, octinoxate, and octocrylene, have been identified as potential risks.

Earlier this year, the National Academies of Sciences, Engineering, and Medicine created a committee to review the existing science about the potential environmental hazards. Over the next 2 years, they’ll also consider the public health implications if people stopped using sunscreen.

Valisure’s announcement included this message: “It is important to note that not all sunscreen products contain benzene and that uncontaminated products are available, should continue to be used, and are important for protecting against potentially harmful solar radiation.”

Using sunscreen with SPF 15 every day can lower risk of squamous cell carcinoma by around 40% and melanoma by 50%. The American Academy of Dermatology recommends a broad-spectrum, water-resistant sunscreen with an SPF of 30 or higher.

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