Nonmelanoma Skin Cancer

The Food and Drug Administration has cleared the DermaSensor device for point-of-care, noninvasive testing for all types of skin cancer.

The handheld wireless tool, which was developed by Miami-based DermaSensor Inc., operates on battery power, uses spectroscopy and algorithms to evaluate skin lesions for potential cancer in a matter of seconds, and is intended for use by primary care physicians. After the device completes the scan of a lesion, a result of “investigate further” (positive result) suggests further evaluation through a referral to a dermatologist, while “monitor” (negative result) suggests that there is no immediate need for a referral to a dermatologist.

In a pivotal trial of the device that evaluated 224 high risk lesions at 18 primary care study sites in the United States and 4 in Australia, the device had an overall sensitivity of 95.5% for detecting malignancy.

In a more recent validation study funded by DermaSensor, investigators tested 333 lesions at four U.S. dermatology offices and found that the overall device sensitivity was 97.04%, with subgroup sensitivity of 96.67% for melanoma, 97.22% for basal cell carcinoma, and 97.01% for squamous cell carcinoma. Overall specificity of the device was 26.22%.

The study authors, led by Tallahassee, Fla.–based dermatologist Armand B. Cognetta Jr., MD, concluded that DermaSensor’s rapid clinical analysis of lesions “allows for its easy integration into clinical practice infrastructures. Proper use of this device may aid in the reduction of morbidity and mortality associated with skin cancer through expedited and enhanced detection and intervention.”

According to marketing material from the DermaSensor website, the device’s AI algorithm was developed and validated with more than 20,000 scans, composed of more than 4,000 benign and malignant lesions. In a statement about the clearance, the FDA emphasized that the device “should not be used as the sole diagnostic criterion nor to confirm a diagnosis of skin cancer.” The agency is requiring that the manufacturer “conduct additional post-market clinical validation performance testing of the DermaSensor device in patients from demographic groups representative of the U.S. population, including populations who had limited representation of melanomas in the premarket studies, due to their having a relatively low incidence of the disease.”

According to a spokesperson for DermaSensor, pricing for the device is based on a subscription model: $199 per month for five patients or $399 per month for unlimited use. DermaSensor is currently commercially available in Europe and Australia.

Asked to comment, Vishal A. Patel, MD, director of cutaneous oncology at the George Washington Cancer Center, Washington, said that the FDA clearance of DermaSensor highlights the growing appreciation of AI-driven diagnostic support for primary care providers and dermatologists. "Skin cancers are a growing epidemic in the US and the ability to accurately identify potential suspicious lesions without immediately reaching for the scalpel is invaluable," Patel told this news organization. He was not involved with DermSensor studies.

"Furthermore, this tool can help address the shortage of dermatologists and long wait times by helping primary care providers accurately risk-stratify patients and identify those who need to be seen immediately for potential biopsy and expert care," he added. "However, just like with any new technology, we must use caution to not overutilize this tool," which he said, could "lead to overdiagnosis and overtreatment of early or innocuous lesions that are better managed with empiric field treatments." 

Dr. Cognetta was a paid investigator for the study.

Dr. Patel disclosed that he is chief medical officer for Lazarus AI.

The Food and Drug Administration has cleared the DermaSensor device for point-of-care, noninvasive testing for all types of skin cancer.

The handheld wireless tool, which was developed by Miami-based DermaSensor Inc., operates on battery power, uses spectroscopy and algorithms to evaluate skin lesions for potential cancer in a matter of seconds, and is intended for use by primary care physicians. After the device completes the scan of a lesion, a result of “investigate further” (positive result) suggests further evaluation through a referral to a dermatologist, while “monitor” (negative result) suggests that there is no immediate need for a referral to a dermatologist.

In a pivotal trial of the device that evaluated 224 high risk lesions at 18 primary care study sites in the United States and 4 in Australia, the device had an overall sensitivity of 95.5% for detecting malignancy.

In a more recent validation study funded by DermaSensor, investigators tested 333 lesions at four U.S. dermatology offices and found that the overall device sensitivity was 97.04%, with subgroup sensitivity of 96.67% for melanoma, 97.22% for basal cell carcinoma, and 97.01% for squamous cell carcinoma. Overall specificity of the device was 26.22%.

The study authors, led by Tallahassee, Fla.–based dermatologist Armand B. Cognetta Jr., MD, concluded that DermaSensor’s rapid clinical analysis of lesions “allows for its easy integration into clinical practice infrastructures. Proper use of this device may aid in the reduction of morbidity and mortality associated with skin cancer through expedited and enhanced detection and intervention.”

According to marketing material from the DermaSensor website, the device’s AI algorithm was developed and validated with more than 20,000 scans, composed of more than 4,000 benign and malignant lesions. In a statement about the clearance, the FDA emphasized that the device “should not be used as the sole diagnostic criterion nor to confirm a diagnosis of skin cancer.” The agency is requiring that the manufacturer “conduct additional post-market clinical validation performance testing of the DermaSensor device in patients from demographic groups representative of the U.S. population, including populations who had limited representation of melanomas in the premarket studies, due to their having a relatively low incidence of the disease.”

According to a spokesperson for DermaSensor, pricing for the device is based on a subscription model: $199 per month for five patients or $399 per month for unlimited use. DermaSensor is currently commercially available in Europe and Australia.

Asked to comment, Vishal A. Patel, MD, director of cutaneous oncology at the George Washington Cancer Center, Washington, said that the FDA clearance of DermaSensor highlights the growing appreciation of AI-driven diagnostic support for primary care providers and dermatologists. "Skin cancers are a growing epidemic in the US and the ability to accurately identify potential suspicious lesions without immediately reaching for the scalpel is invaluable," Patel told this news organization. He was not involved with DermSensor studies.

"Furthermore, this tool can help address the shortage of dermatologists and long wait times by helping primary care providers accurately risk-stratify patients and identify those who need to be seen immediately for potential biopsy and expert care," he added. "However, just like with any new technology, we must use caution to not overutilize this tool," which he said, could "lead to overdiagnosis and overtreatment of early or innocuous lesions that are better managed with empiric field treatments." 

Dr. Cognetta was a paid investigator for the study.

Dr. Patel disclosed that he is chief medical officer for Lazarus AI.

The Food and Drug Administration has cleared the DermaSensor device for point-of-care, noninvasive testing for all types of skin cancer.

The handheld wireless tool, which was developed by Miami-based DermaSensor Inc., operates on battery power, uses spectroscopy and algorithms to evaluate skin lesions for potential cancer in a matter of seconds, and is intended for use by primary care physicians. After the device completes the scan of a lesion, a result of “investigate further” (positive result) suggests further evaluation through a referral to a dermatologist, while “monitor” (negative result) suggests that there is no immediate need for a referral to a dermatologist.

In a pivotal trial of the device that evaluated 224 high risk lesions at 18 primary care study sites in the United States and 4 in Australia, the device had an overall sensitivity of 95.5% for detecting malignancy.

In a more recent validation study funded by DermaSensor, investigators tested 333 lesions at four U.S. dermatology offices and found that the overall device sensitivity was 97.04%, with subgroup sensitivity of 96.67% for melanoma, 97.22% for basal cell carcinoma, and 97.01% for squamous cell carcinoma. Overall specificity of the device was 26.22%.

The study authors, led by Tallahassee, Fla.–based dermatologist Armand B. Cognetta Jr., MD, concluded that DermaSensor’s rapid clinical analysis of lesions “allows for its easy integration into clinical practice infrastructures. Proper use of this device may aid in the reduction of morbidity and mortality associated with skin cancer through expedited and enhanced detection and intervention.”

According to marketing material from the DermaSensor website, the device’s AI algorithm was developed and validated with more than 20,000 scans, composed of more than 4,000 benign and malignant lesions. In a statement about the clearance, the FDA emphasized that the device “should not be used as the sole diagnostic criterion nor to confirm a diagnosis of skin cancer.” The agency is requiring that the manufacturer “conduct additional post-market clinical validation performance testing of the DermaSensor device in patients from demographic groups representative of the U.S. population, including populations who had limited representation of melanomas in the premarket studies, due to their having a relatively low incidence of the disease.”

According to a spokesperson for DermaSensor, pricing for the device is based on a subscription model: $199 per month for five patients or $399 per month for unlimited use. DermaSensor is currently commercially available in Europe and Australia.

Asked to comment, Vishal A. Patel, MD, director of cutaneous oncology at the George Washington Cancer Center, Washington, said that the FDA clearance of DermaSensor highlights the growing appreciation of AI-driven diagnostic support for primary care providers and dermatologists. "Skin cancers are a growing epidemic in the US and the ability to accurately identify potential suspicious lesions without immediately reaching for the scalpel is invaluable," Patel told this news organization. He was not involved with DermSensor studies.

"Furthermore, this tool can help address the shortage of dermatologists and long wait times by helping primary care providers accurately risk-stratify patients and identify those who need to be seen immediately for potential biopsy and expert care," he added. "However, just like with any new technology, we must use caution to not overutilize this tool," which he said, could "lead to overdiagnosis and overtreatment of early or innocuous lesions that are better managed with empiric field treatments." 

Dr. Cognetta was a paid investigator for the study.

Dr. Patel disclosed that he is chief medical officer for Lazarus AI.

As many as one-quarter of human cancers are related to chronic inflammation, chronic infection, or both.¹ Extrinsic inflammation leads to generation of proinflammatory cytokines that in turn recruit other inflammatory cells, which is thought to generate a positive amplification loop.² Intrinsic stimuli from proto-oncogenes and mutations in tumor suppressor genes lead to transformed cancer cells that also secrete proinflammatory cytokines, thus propagating the cycle.

Numerous factors have been observed in association with tumor growth, progression, invasion, and metastasis.³ One factor for the development of squamous cell carcinoma (SCC) may be chronic inflammatory dermatoses. To date, reviews of chronic inflammation–associated malignancy have focused on solid organ cancers. We sought to provide an up-to-date review of SCC arising within chronic dermatoses, with an emphasis on the anatomic location of dermatoses involved in the transformation of cancer cells, the lag time from onset of dermatosis to diagnosis of SCC, and the distinctive mechanisms thought to be involved in the tumorigenesis in particular dermatoses.

Discoid Lupus Erythematosus

Discoid lupus erythematosus (DLE) is a chronic cutaneous lupus erythematosus variant with a female to male predominance of 3:1,⁴ and DLE lesions are prone to malignant transformation. Retrospective cohort studies have attempted to characterize who is at risk for SCC and how SCCs behave depending on their location. Cohorts from China,⁵ India,⁶ and Japan⁷ have noted a higher rate of SCC within DLE lesions in men (female to male ratios of 1:2.2, 1:1.6, and 1:2, respectively) and shorter lag times for SCC onset within DLE lesions of the lips (13, 5, and 10 years, respectively) compared to SCC arising in DLE elsewhere (19.2, 11.2, and 26 years, respectively). Studies have noted that DLE lesions of the lips may be prone to more rapid SCC tumorigenesis compared to DLE on cutaneous sites. One study reported SCC in DLE recurrence, metastasis, and death rates of 29%, 16.1%, and 19.4%, respectively,⁵ which exceeds reported rates in non-DLE SCCs (20%, 0.5% to 6%, and 1%, respectively).^5,8

Because SCC arising within DLE is most common on the lips (Figure 1), it has been hypothesized that the high rate of transformation of DLE lesions on the lips may be due to constant exposure to irritation and tobacco, which may accelerate carcinogenesis.⁵ It also has been hypothesized that atrophic discoid lesions have lost sun protection and are more prone to mutagenic UV radiation,⁹ as SCCs arising in DLE lesions virtually always display prominent solar elastosis⁶; however, SCC has been observed to arise in non–sun-exposed DLE lesions in both White and Black patients.¹⁰

Photograph courtesy of Andrea Murina, MD.

Additionally, use of immunosuppressant medications may accelerate the emergence of malignancy or more aggressive forms of malignancy; however, patients with autoimmune disease have a greater risk for malignancy at baseline,¹¹ thus making it difficult to determine the excess risk from medications. There also may be a role for human papillomavirus (HPV) accelerating SCC development in DLE lesions, as demonstrated in a case of SCC arising in DLE lesions of the ears, with viral staining evident within the tumors.¹² However, testing for HPV is not routinely performed in these cases.

Dermatologists need to be aware of the relatively rapid tumorigenesis and aggressive behavior of transformation and aggression seen with SCC arising within orolabial DLE lesions compared to cutaneous lesions, especially those on the lips.

Lichen Planus

Although patients with typical cutaneous lichen planus lesions do not have an increased risk for SCC,¹³ variants of lichen planus may predispose patients to SCC.

Oral Lichen Planus—Oral lichen planus (OLP) lesions are prone to malignant transformation. A systematic review of 16 studies evaluating the risk for OLP-associated SCC revealed an overall transformation rate of 1.09%, with a mean lag time of 4.3 years,¹⁴ compared to a reference rate of 0.2% for oral SCC.¹⁵ A meta-analysis of 19,676 patients with OLP and other oral lichenoid lesions revealed an oral SCC rate of 1.1%, with higher rates of transformation seen in cigarette smokers, alcoholics, and patients with hepatitis C virus infection.¹⁶ The ulcerative subtype of OLP appears to present a greater risk for malignant transformation.¹⁵ Dermatologists also should be cognizant that treatments for OLP such as topical calcineurin inhibitors may support the development of malignancy within inflammatory lesions.¹⁷

Hypertrophic Lichen Planus—The hypertrophic variant of lichen planus (HLP) also is prone to malignant transformation. A 1991 epidemiologic study from Sweden of malignancy arising in lichen planus revealed a disproportionate number of cases arising in verrucous or hypertrophic lesions, with a mean of 12.2 years from onset of the dermatosis to malignancy diagnosis.¹³ A subsequent 2015 retrospective study of 38 patients revealed that SCC had a propensity for the lower limb, favoring the pretibial region and the calf over the foot and the ankle with a reported lag time of 11 years.¹⁸

Although metastatic SCC arising in HLP is rare, 2 cases have been reported. A 24-year-old woman presented with an HLP plaque on the lower leg that developed during childhood and rapidly enlarged 2 months prior to presentation; she eventually died from metastatic disease.¹⁹ In another case, a 34-year-old man presented with an HLP lesion of approximately 10 years’ duration. A well-differentiated SCC was excised, and he developed lymph node metastases 5 months later.²⁰

It is important to note that HLP on the legs often is misdiagnosed as SCC, as pseudoepitheliomatous hyperplasia and squamous metaplasia can be difficult to differentiate clinically and histologically.^21,22 In the case of multiple eruptive SCCs of the lower leg, clinical correlation is essential to avoid unnecessary and ineffective surgical treatment.

Patients with HLP may exhibit Wickham striae, follicular accentuation, and mucocutaneous lichen planus at other sites, or a correlative initiation of possible culprit medications.²³ Because true SCC arising within HLP is relatively rare, its malignant potential is not as clear as those arising within DLE; however, the lower limb appears to be the most common location for SCC within HLP.Nail Lichen Planus—Squamous cell carcinoma arising in nail lichen planus is rare. A report of 2 patients were diagnosed with lichen planus approximately 15 years prior to diagnosis of ungual SCC.²⁴ Given the rarity of this presentation, it is difficult to ascertain the approximate lag time and other risk factors. Furthermore, the role of HPV in these cases was not ruled out. Oncogenic HPV strains have been reported in patients with periungual SCC.^25,26

Lichen Sclerosus

Lichen sclerosus (LS) is a chronic inflammatory dermatosis that favors the anogenital area in a female to male ratio of 10:1.²⁷ It is considered a premalignant condition for SCC tumorigenesis and may be a strong predictor of vulvar SCC (Figure 2), as 62% of vulvar SCC cases (N=78) may have adjacent LS.²⁸

Photograph courtesy of Laura C. Williams, MD (New Orleans, Louisiana).

In a Dutch cohort of 3038 women with LS, 2.6% of patients developed vulvar SCC at a median of 3.3 years after LS diagnosis.²⁹ Other studies have estimated a lag time of 4 years until SCC presentation.³⁰ An Italian cohort of 976 women similarly observed that 2.7% of patients developed premalignancy or SCC.³¹ It was previously estimated that 3% to 5% of patients with LS developed SCC; however, prior studies may have included cases of vulvar intraepithelial neoplasia with low risk for invasive SCC, which might have overestimated true risk of SCC.³² Another confounding factor for elucidating SCC on a background of LS may be the presence of HPV.³³ Extragenital LS does not appear to have similar potential for malignant transformation.³⁴

In a prospective Australian cohort of 507 women with LS (mean age, 55.4 years), remission was induced with potent topical corticosteroids.³⁵ Patients who were adherent to a topical regimen did not develop SCC during follow-up. Those who were nonadherent or partially adherent had a 4.7% risk for SCC.³⁵ In a similar prospective study of 83 women in France, the SCC rate was 9.6% in lesions that were untreated or irregularly treated.³⁶ These studies provide essential evidence that appropriately treating LS can prevent SCC at a later date, though longer-term data are lacking.

The rate of SCC arising in male genital LS may approach 8.4%,³⁷ with a lag time of 17 years from onset of LS to SCC diagnosis.³⁸ Although circumcision often is considered curative for male genital LS, patients have been observed to develop penile SCC at least 5 years after circumcision.³⁹ Male penile SCC in a background of LS may not necessarily be HPV associated.⁴⁰

Marjolin Ulcer

Chronic ulcers or scars, typically postburn scars, may undergo malignant transformation, with SCC being the most common carcinoma.⁴¹ Squamous cell carcinoma in the context of a chronic ulcer or wound is known as a Marjolin ulcer (MU). Up to 2% of burn scars have been observed to undergo malignant transformation.⁴² Marjolin ulcers tend to behave aggressively once they form, and it has been proposed that removal of scar tissue may be a preventive therapeutic strategy.⁴³ Cohort studies of MU on the lower extremities have observed lag times of 26.4⁴⁴ and 37.9⁴⁵ years, with both studies also noting relatively high rates of local recurrence.

The pathogenesis of MU appears to be multifactorial. Chronic inflammation and scar formation have been implicated. Chronic inflammation and irritation of lesions at natural creases are thought to increase mitotic activity,⁴¹ and local accumulation of toxin may promote mutagenesis.⁴⁶ Scar formation may create a locally immunoprivileged site, allowing for developing tumors to evade the immune system⁴⁷ and become even more aggressive as the tumor accumulates.⁴⁸ Scar formation also may prevent the ability of immune cells to penetrate the tumor microenvironment and access lymphatic channels.⁴⁹

Hidradenitis Suppurativa

As many as 3.2% of patients with chronic hidradenitis suppurativa (HS) experience malignant transformation to SCC.⁵⁰ Early HS displays subclinical lymphedema in affected sites, which can progress to chronic fibrosis, stasis, and accumulation of protein-rich fluid.⁵¹ Stasis changes have been associated with altered local inflammatory proteins, such as toll-like receptors, β-defensins, and interleukins.⁵²

A retrospective cohort study of 12 patients revealed a lag time of 28.5 years from HS diagnosis to the manifestation of malignancy.⁵³ After local excision, 7 patients developed recurrence, with 100% mortality. Squamous cell carcinomas were well differentiated and moderately differentiated.⁵³ A 2017 literature review of 62 case reports calculated a mean lag time of 27 years. Despite 85% of SCCs being well differentiated and moderately differentiated, nearly half of patients died within 2 years.⁵⁴ As seen in other inflammatory conditions, HPV can complicate perineal HS and promote SCC tumorigenesis.⁵⁵

Squamous cell carcinomas arising within HS lesions are more prevalent in males (6.75:1 ratio),^54,56 despite HS being more prevalent in females (2:1 ratio).⁵⁷ Similar to DLE, SCCs arising in HS are aggressive and are seen more in males, despite both conditions being female predominant. Incidence and mortality rates for primary cutaneous SCC are higher for men vs women⁵⁸; however, the discordance in aggressive behavior seen more commonly in SCC arising from HS or DLE in male patients has yet to be explained.

Malignancy arising within necrobiosis lipoidica diabeticorum (NLD) is rare. A review of 14 published cases noted that 13 were SCC and 1 was leiomyosarcoma.⁵⁹ The lag time was 21.5 years; 31% of cases (N=14) presented with regional lymph node metastasis. Although chronic ulceration is a risk factor for SCC and occurs in as many as one-third of NLD cases, its correlation with ulceration and malignant transformation has not been characterized.

Epidermolysis Bullosa

Recessive dystrophic epidermolysis bullosa (RDEB) is a noninflammatory inherited blistering disease, and patients have an inherently high risk for aggressive SCC.⁶⁰ Other forms of epidermolysis bullosa can lead to SCC, but the rarer RDEB accounts for 69% of SCC cases, with a median age of 36 years at presentation.⁶¹ Although SCCs tend to be well differentiated in RDEB (73.9%),⁶¹ they also exhibit highly aggressive behavior.⁶² In the most severe variant—RDEB-generalized severe—the cumulative risk for SCC-related death in an Australian population was 84.4% at 34 years of age.⁶³

As RDEB is an inherited disorder with potential for malignancy at a young age, the pathogenesis is plausibly different from the previously discussed inflammatory dermatoses. This disease is characterized by a mutation in the collagen VII gene, leading to loss of anchoring fibrils and a basement membrane zone split.⁶⁴ There also can be inherent fibroblast alterations; RDEB fibroblasts create an environment for tumor growth by supporting malignant-cell adhesion and invasion.⁶⁵ Mutations in p53,⁶⁶ local alterations in transforming growth factor β activity,⁶⁷ and downstream matrix metalloproteinase activity⁶⁸ have been implicated.

Additionally, keratinocytes may retain the N-terminal noncollagenous (NC1) domain of truncated collagen VII while losing the anchoring NC2 domain in mutated collagen VII RDEB, thereby supporting anchorless keratinocyte survival and higher metastatic potential.⁶⁹ Retention of this truncated NC1 domain has shown conversion of RDEB keratinocytes to tumor in a xenotransplant mouse model.⁷⁰ A high level of type VII collagen itself may inherently be protumorigenic for keratinocytes.⁷¹

There does not appear to be evidence for HPV involvement in RDEB-associated SCC.⁷² Squamous cell carcinoma development in RDEB appears to be multifactorial,⁷³ but validated tumor models are lacking. Other than conventional oncologic therapy, future directions in the management of RDEB may include gene-, protein- and cell-targeted therapies.⁷³

Conclusion

Squamous cell carcinomas are known to arise within chronic cutaneous inflammatory dermatoses. Tumorigenesis peaks relatively early in new orolabial DLE, LS, and OLP cases, and can occur over many decades in cutaneous DLE, HLP, HS, NLD, and chronic wounds or scars, summarized in the Table. Frequent SCCs are observed in high-risk subtypes of epidermolysis bullosa. Dermatologists must examine areas affected by these diseases at regular intervals, being mindful of the possibility of SCC development. Furthermore, dermatologists should adopt a lower threshold to biopsy suspicious lesions, especially those that develop within relatively new orolabial DLE, chronic HS, or chronic wound cases, as SCC in these settings is particularly aggressive and displays mortality and metastasis rates that exceed those of common cutaneous SCC.


As many as one-quarter of human cancers are related to chronic inflammation, chronic infection, or both.¹ Extrinsic inflammation leads to generation of proinflammatory cytokines that in turn recruit other inflammatory cells, which is thought to generate a positive amplification loop.² Intrinsic stimuli from proto-oncogenes and mutations in tumor suppressor genes lead to transformed cancer cells that also secrete proinflammatory cytokines, thus propagating the cycle.

Numerous factors have been observed in association with tumor growth, progression, invasion, and metastasis.³ One factor for the development of squamous cell carcinoma (SCC) may be chronic inflammatory dermatoses. To date, reviews of chronic inflammation–associated malignancy have focused on solid organ cancers. We sought to provide an up-to-date review of SCC arising within chronic dermatoses, with an emphasis on the anatomic location of dermatoses involved in the transformation of cancer cells, the lag time from onset of dermatosis to diagnosis of SCC, and the distinctive mechanisms thought to be involved in the tumorigenesis in particular dermatoses.

Discoid Lupus Erythematosus

Discoid lupus erythematosus (DLE) is a chronic cutaneous lupus erythematosus variant with a female to male predominance of 3:1,⁴ and DLE lesions are prone to malignant transformation. Retrospective cohort studies have attempted to characterize who is at risk for SCC and how SCCs behave depending on their location. Cohorts from China,⁵ India,⁶ and Japan⁷ have noted a higher rate of SCC within DLE lesions in men (female to male ratios of 1:2.2, 1:1.6, and 1:2, respectively) and shorter lag times for SCC onset within DLE lesions of the lips (13, 5, and 10 years, respectively) compared to SCC arising in DLE elsewhere (19.2, 11.2, and 26 years, respectively). Studies have noted that DLE lesions of the lips may be prone to more rapid SCC tumorigenesis compared to DLE on cutaneous sites. One study reported SCC in DLE recurrence, metastasis, and death rates of 29%, 16.1%, and 19.4%, respectively,⁵ which exceeds reported rates in non-DLE SCCs (20%, 0.5% to 6%, and 1%, respectively).^5,8

Because SCC arising within DLE is most common on the lips (Figure 1), it has been hypothesized that the high rate of transformation of DLE lesions on the lips may be due to constant exposure to irritation and tobacco, which may accelerate carcinogenesis.⁵ It also has been hypothesized that atrophic discoid lesions have lost sun protection and are more prone to mutagenic UV radiation,⁹ as SCCs arising in DLE lesions virtually always display prominent solar elastosis⁶; however, SCC has been observed to arise in non–sun-exposed DLE lesions in both White and Black patients.¹⁰

Photograph courtesy of Andrea Murina, MD.

Additionally, use of immunosuppressant medications may accelerate the emergence of malignancy or more aggressive forms of malignancy; however, patients with autoimmune disease have a greater risk for malignancy at baseline,¹¹ thus making it difficult to determine the excess risk from medications. There also may be a role for human papillomavirus (HPV) accelerating SCC development in DLE lesions, as demonstrated in a case of SCC arising in DLE lesions of the ears, with viral staining evident within the tumors.¹² However, testing for HPV is not routinely performed in these cases.

Dermatologists need to be aware of the relatively rapid tumorigenesis and aggressive behavior of transformation and aggression seen with SCC arising within orolabial DLE lesions compared to cutaneous lesions, especially those on the lips.

Lichen Planus

Although patients with typical cutaneous lichen planus lesions do not have an increased risk for SCC,¹³ variants of lichen planus may predispose patients to SCC.

Oral Lichen Planus—Oral lichen planus (OLP) lesions are prone to malignant transformation. A systematic review of 16 studies evaluating the risk for OLP-associated SCC revealed an overall transformation rate of 1.09%, with a mean lag time of 4.3 years,¹⁴ compared to a reference rate of 0.2% for oral SCC.¹⁵ A meta-analysis of 19,676 patients with OLP and other oral lichenoid lesions revealed an oral SCC rate of 1.1%, with higher rates of transformation seen in cigarette smokers, alcoholics, and patients with hepatitis C virus infection.¹⁶ The ulcerative subtype of OLP appears to present a greater risk for malignant transformation.¹⁵ Dermatologists also should be cognizant that treatments for OLP such as topical calcineurin inhibitors may support the development of malignancy within inflammatory lesions.¹⁷

Hypertrophic Lichen Planus—The hypertrophic variant of lichen planus (HLP) also is prone to malignant transformation. A 1991 epidemiologic study from Sweden of malignancy arising in lichen planus revealed a disproportionate number of cases arising in verrucous or hypertrophic lesions, with a mean of 12.2 years from onset of the dermatosis to malignancy diagnosis.¹³ A subsequent 2015 retrospective study of 38 patients revealed that SCC had a propensity for the lower limb, favoring the pretibial region and the calf over the foot and the ankle with a reported lag time of 11 years.¹⁸

Although metastatic SCC arising in HLP is rare, 2 cases have been reported. A 24-year-old woman presented with an HLP plaque on the lower leg that developed during childhood and rapidly enlarged 2 months prior to presentation; she eventually died from metastatic disease.¹⁹ In another case, a 34-year-old man presented with an HLP lesion of approximately 10 years’ duration. A well-differentiated SCC was excised, and he developed lymph node metastases 5 months later.²⁰

It is important to note that HLP on the legs often is misdiagnosed as SCC, as pseudoepitheliomatous hyperplasia and squamous metaplasia can be difficult to differentiate clinically and histologically.^21,22 In the case of multiple eruptive SCCs of the lower leg, clinical correlation is essential to avoid unnecessary and ineffective surgical treatment.

Patients with HLP may exhibit Wickham striae, follicular accentuation, and mucocutaneous lichen planus at other sites, or a correlative initiation of possible culprit medications.²³ Because true SCC arising within HLP is relatively rare, its malignant potential is not as clear as those arising within DLE; however, the lower limb appears to be the most common location for SCC within HLP.Nail Lichen Planus—Squamous cell carcinoma arising in nail lichen planus is rare. A report of 2 patients were diagnosed with lichen planus approximately 15 years prior to diagnosis of ungual SCC.²⁴ Given the rarity of this presentation, it is difficult to ascertain the approximate lag time and other risk factors. Furthermore, the role of HPV in these cases was not ruled out. Oncogenic HPV strains have been reported in patients with periungual SCC.^25,26

Lichen Sclerosus

Lichen sclerosus (LS) is a chronic inflammatory dermatosis that favors the anogenital area in a female to male ratio of 10:1.²⁷ It is considered a premalignant condition for SCC tumorigenesis and may be a strong predictor of vulvar SCC (Figure 2), as 62% of vulvar SCC cases (N=78) may have adjacent LS.²⁸

Photograph courtesy of Laura C. Williams, MD (New Orleans, Louisiana).

In a Dutch cohort of 3038 women with LS, 2.6% of patients developed vulvar SCC at a median of 3.3 years after LS diagnosis.²⁹ Other studies have estimated a lag time of 4 years until SCC presentation.³⁰ An Italian cohort of 976 women similarly observed that 2.7% of patients developed premalignancy or SCC.³¹ It was previously estimated that 3% to 5% of patients with LS developed SCC; however, prior studies may have included cases of vulvar intraepithelial neoplasia with low risk for invasive SCC, which might have overestimated true risk of SCC.³² Another confounding factor for elucidating SCC on a background of LS may be the presence of HPV.³³ Extragenital LS does not appear to have similar potential for malignant transformation.³⁴

In a prospective Australian cohort of 507 women with LS (mean age, 55.4 years), remission was induced with potent topical corticosteroids.³⁵ Patients who were adherent to a topical regimen did not develop SCC during follow-up. Those who were nonadherent or partially adherent had a 4.7% risk for SCC.³⁵ In a similar prospective study of 83 women in France, the SCC rate was 9.6% in lesions that were untreated or irregularly treated.³⁶ These studies provide essential evidence that appropriately treating LS can prevent SCC at a later date, though longer-term data are lacking.

The rate of SCC arising in male genital LS may approach 8.4%,³⁷ with a lag time of 17 years from onset of LS to SCC diagnosis.³⁸ Although circumcision often is considered curative for male genital LS, patients have been observed to develop penile SCC at least 5 years after circumcision.³⁹ Male penile SCC in a background of LS may not necessarily be HPV associated.⁴⁰

Marjolin Ulcer

Chronic ulcers or scars, typically postburn scars, may undergo malignant transformation, with SCC being the most common carcinoma.⁴¹ Squamous cell carcinoma in the context of a chronic ulcer or wound is known as a Marjolin ulcer (MU). Up to 2% of burn scars have been observed to undergo malignant transformation.⁴² Marjolin ulcers tend to behave aggressively once they form, and it has been proposed that removal of scar tissue may be a preventive therapeutic strategy.⁴³ Cohort studies of MU on the lower extremities have observed lag times of 26.4⁴⁴ and 37.9⁴⁵ years, with both studies also noting relatively high rates of local recurrence.

The pathogenesis of MU appears to be multifactorial. Chronic inflammation and scar formation have been implicated. Chronic inflammation and irritation of lesions at natural creases are thought to increase mitotic activity,⁴¹ and local accumulation of toxin may promote mutagenesis.⁴⁶ Scar formation may create a locally immunoprivileged site, allowing for developing tumors to evade the immune system⁴⁷ and become even more aggressive as the tumor accumulates.⁴⁸ Scar formation also may prevent the ability of immune cells to penetrate the tumor microenvironment and access lymphatic channels.⁴⁹

Hidradenitis Suppurativa

As many as 3.2% of patients with chronic hidradenitis suppurativa (HS) experience malignant transformation to SCC.⁵⁰ Early HS displays subclinical lymphedema in affected sites, which can progress to chronic fibrosis, stasis, and accumulation of protein-rich fluid.⁵¹ Stasis changes have been associated with altered local inflammatory proteins, such as toll-like receptors, β-defensins, and interleukins.⁵²

A retrospective cohort study of 12 patients revealed a lag time of 28.5 years from HS diagnosis to the manifestation of malignancy.⁵³ After local excision, 7 patients developed recurrence, with 100% mortality. Squamous cell carcinomas were well differentiated and moderately differentiated.⁵³ A 2017 literature review of 62 case reports calculated a mean lag time of 27 years. Despite 85% of SCCs being well differentiated and moderately differentiated, nearly half of patients died within 2 years.⁵⁴ As seen in other inflammatory conditions, HPV can complicate perineal HS and promote SCC tumorigenesis.⁵⁵

Squamous cell carcinomas arising within HS lesions are more prevalent in males (6.75:1 ratio),^54,56 despite HS being more prevalent in females (2:1 ratio).⁵⁷ Similar to DLE, SCCs arising in HS are aggressive and are seen more in males, despite both conditions being female predominant. Incidence and mortality rates for primary cutaneous SCC are higher for men vs women⁵⁸; however, the discordance in aggressive behavior seen more commonly in SCC arising from HS or DLE in male patients has yet to be explained.

Malignancy arising within necrobiosis lipoidica diabeticorum (NLD) is rare. A review of 14 published cases noted that 13 were SCC and 1 was leiomyosarcoma.⁵⁹ The lag time was 21.5 years; 31% of cases (N=14) presented with regional lymph node metastasis. Although chronic ulceration is a risk factor for SCC and occurs in as many as one-third of NLD cases, its correlation with ulceration and malignant transformation has not been characterized.

Epidermolysis Bullosa

Recessive dystrophic epidermolysis bullosa (RDEB) is a noninflammatory inherited blistering disease, and patients have an inherently high risk for aggressive SCC.⁶⁰ Other forms of epidermolysis bullosa can lead to SCC, but the rarer RDEB accounts for 69% of SCC cases, with a median age of 36 years at presentation.⁶¹ Although SCCs tend to be well differentiated in RDEB (73.9%),⁶¹ they also exhibit highly aggressive behavior.⁶² In the most severe variant—RDEB-generalized severe—the cumulative risk for SCC-related death in an Australian population was 84.4% at 34 years of age.⁶³

As RDEB is an inherited disorder with potential for malignancy at a young age, the pathogenesis is plausibly different from the previously discussed inflammatory dermatoses. This disease is characterized by a mutation in the collagen VII gene, leading to loss of anchoring fibrils and a basement membrane zone split.⁶⁴ There also can be inherent fibroblast alterations; RDEB fibroblasts create an environment for tumor growth by supporting malignant-cell adhesion and invasion.⁶⁵ Mutations in p53,⁶⁶ local alterations in transforming growth factor β activity,⁶⁷ and downstream matrix metalloproteinase activity⁶⁸ have been implicated.

Additionally, keratinocytes may retain the N-terminal noncollagenous (NC1) domain of truncated collagen VII while losing the anchoring NC2 domain in mutated collagen VII RDEB, thereby supporting anchorless keratinocyte survival and higher metastatic potential.⁶⁹ Retention of this truncated NC1 domain has shown conversion of RDEB keratinocytes to tumor in a xenotransplant mouse model.⁷⁰ A high level of type VII collagen itself may inherently be protumorigenic for keratinocytes.⁷¹

There does not appear to be evidence for HPV involvement in RDEB-associated SCC.⁷² Squamous cell carcinoma development in RDEB appears to be multifactorial,⁷³ but validated tumor models are lacking. Other than conventional oncologic therapy, future directions in the management of RDEB may include gene-, protein- and cell-targeted therapies.⁷³

Conclusion

Squamous cell carcinomas are known to arise within chronic cutaneous inflammatory dermatoses. Tumorigenesis peaks relatively early in new orolabial DLE, LS, and OLP cases, and can occur over many decades in cutaneous DLE, HLP, HS, NLD, and chronic wounds or scars, summarized in the Table. Frequent SCCs are observed in high-risk subtypes of epidermolysis bullosa. Dermatologists must examine areas affected by these diseases at regular intervals, being mindful of the possibility of SCC development. Furthermore, dermatologists should adopt a lower threshold to biopsy suspicious lesions, especially those that develop within relatively new orolabial DLE, chronic HS, or chronic wound cases, as SCC in these settings is particularly aggressive and displays mortality and metastasis rates that exceed those of common cutaneous SCC.


As many as one-quarter of human cancers are related to chronic inflammation, chronic infection, or both.¹ Extrinsic inflammation leads to generation of proinflammatory cytokines that in turn recruit other inflammatory cells, which is thought to generate a positive amplification loop.² Intrinsic stimuli from proto-oncogenes and mutations in tumor suppressor genes lead to transformed cancer cells that also secrete proinflammatory cytokines, thus propagating the cycle.

Numerous factors have been observed in association with tumor growth, progression, invasion, and metastasis.³ One factor for the development of squamous cell carcinoma (SCC) may be chronic inflammatory dermatoses. To date, reviews of chronic inflammation–associated malignancy have focused on solid organ cancers. We sought to provide an up-to-date review of SCC arising within chronic dermatoses, with an emphasis on the anatomic location of dermatoses involved in the transformation of cancer cells, the lag time from onset of dermatosis to diagnosis of SCC, and the distinctive mechanisms thought to be involved in the tumorigenesis in particular dermatoses.

Discoid Lupus Erythematosus

Discoid lupus erythematosus (DLE) is a chronic cutaneous lupus erythematosus variant with a female to male predominance of 3:1,⁴ and DLE lesions are prone to malignant transformation. Retrospective cohort studies have attempted to characterize who is at risk for SCC and how SCCs behave depending on their location. Cohorts from China,⁵ India,⁶ and Japan⁷ have noted a higher rate of SCC within DLE lesions in men (female to male ratios of 1:2.2, 1:1.6, and 1:2, respectively) and shorter lag times for SCC onset within DLE lesions of the lips (13, 5, and 10 years, respectively) compared to SCC arising in DLE elsewhere (19.2, 11.2, and 26 years, respectively). Studies have noted that DLE lesions of the lips may be prone to more rapid SCC tumorigenesis compared to DLE on cutaneous sites. One study reported SCC in DLE recurrence, metastasis, and death rates of 29%, 16.1%, and 19.4%, respectively,⁵ which exceeds reported rates in non-DLE SCCs (20%, 0.5% to 6%, and 1%, respectively).^5,8

Because SCC arising within DLE is most common on the lips (Figure 1), it has been hypothesized that the high rate of transformation of DLE lesions on the lips may be due to constant exposure to irritation and tobacco, which may accelerate carcinogenesis.⁵ It also has been hypothesized that atrophic discoid lesions have lost sun protection and are more prone to mutagenic UV radiation,⁹ as SCCs arising in DLE lesions virtually always display prominent solar elastosis⁶; however, SCC has been observed to arise in non–sun-exposed DLE lesions in both White and Black patients.¹⁰

Photograph courtesy of Andrea Murina, MD.

Additionally, use of immunosuppressant medications may accelerate the emergence of malignancy or more aggressive forms of malignancy; however, patients with autoimmune disease have a greater risk for malignancy at baseline,¹¹ thus making it difficult to determine the excess risk from medications. There also may be a role for human papillomavirus (HPV) accelerating SCC development in DLE lesions, as demonstrated in a case of SCC arising in DLE lesions of the ears, with viral staining evident within the tumors.¹² However, testing for HPV is not routinely performed in these cases.

Dermatologists need to be aware of the relatively rapid tumorigenesis and aggressive behavior of transformation and aggression seen with SCC arising within orolabial DLE lesions compared to cutaneous lesions, especially those on the lips.

Lichen Planus

Although patients with typical cutaneous lichen planus lesions do not have an increased risk for SCC,¹³ variants of lichen planus may predispose patients to SCC.

Oral Lichen Planus—Oral lichen planus (OLP) lesions are prone to malignant transformation. A systematic review of 16 studies evaluating the risk for OLP-associated SCC revealed an overall transformation rate of 1.09%, with a mean lag time of 4.3 years,¹⁴ compared to a reference rate of 0.2% for oral SCC.¹⁵ A meta-analysis of 19,676 patients with OLP and other oral lichenoid lesions revealed an oral SCC rate of 1.1%, with higher rates of transformation seen in cigarette smokers, alcoholics, and patients with hepatitis C virus infection.¹⁶ The ulcerative subtype of OLP appears to present a greater risk for malignant transformation.¹⁵ Dermatologists also should be cognizant that treatments for OLP such as topical calcineurin inhibitors may support the development of malignancy within inflammatory lesions.¹⁷

Hypertrophic Lichen Planus—The hypertrophic variant of lichen planus (HLP) also is prone to malignant transformation. A 1991 epidemiologic study from Sweden of malignancy arising in lichen planus revealed a disproportionate number of cases arising in verrucous or hypertrophic lesions, with a mean of 12.2 years from onset of the dermatosis to malignancy diagnosis.¹³ A subsequent 2015 retrospective study of 38 patients revealed that SCC had a propensity for the lower limb, favoring the pretibial region and the calf over the foot and the ankle with a reported lag time of 11 years.¹⁸

Although metastatic SCC arising in HLP is rare, 2 cases have been reported. A 24-year-old woman presented with an HLP plaque on the lower leg that developed during childhood and rapidly enlarged 2 months prior to presentation; she eventually died from metastatic disease.¹⁹ In another case, a 34-year-old man presented with an HLP lesion of approximately 10 years’ duration. A well-differentiated SCC was excised, and he developed lymph node metastases 5 months later.²⁰

It is important to note that HLP on the legs often is misdiagnosed as SCC, as pseudoepitheliomatous hyperplasia and squamous metaplasia can be difficult to differentiate clinically and histologically.^21,22 In the case of multiple eruptive SCCs of the lower leg, clinical correlation is essential to avoid unnecessary and ineffective surgical treatment.

Patients with HLP may exhibit Wickham striae, follicular accentuation, and mucocutaneous lichen planus at other sites, or a correlative initiation of possible culprit medications.²³ Because true SCC arising within HLP is relatively rare, its malignant potential is not as clear as those arising within DLE; however, the lower limb appears to be the most common location for SCC within HLP.Nail Lichen Planus—Squamous cell carcinoma arising in nail lichen planus is rare. A report of 2 patients were diagnosed with lichen planus approximately 15 years prior to diagnosis of ungual SCC.²⁴ Given the rarity of this presentation, it is difficult to ascertain the approximate lag time and other risk factors. Furthermore, the role of HPV in these cases was not ruled out. Oncogenic HPV strains have been reported in patients with periungual SCC.^25,26

Lichen Sclerosus

Lichen sclerosus (LS) is a chronic inflammatory dermatosis that favors the anogenital area in a female to male ratio of 10:1.²⁷ It is considered a premalignant condition for SCC tumorigenesis and may be a strong predictor of vulvar SCC (Figure 2), as 62% of vulvar SCC cases (N=78) may have adjacent LS.²⁸

Photograph courtesy of Laura C. Williams, MD (New Orleans, Louisiana).

In a Dutch cohort of 3038 women with LS, 2.6% of patients developed vulvar SCC at a median of 3.3 years after LS diagnosis.²⁹ Other studies have estimated a lag time of 4 years until SCC presentation.³⁰ An Italian cohort of 976 women similarly observed that 2.7% of patients developed premalignancy or SCC.³¹ It was previously estimated that 3% to 5% of patients with LS developed SCC; however, prior studies may have included cases of vulvar intraepithelial neoplasia with low risk for invasive SCC, which might have overestimated true risk of SCC.³² Another confounding factor for elucidating SCC on a background of LS may be the presence of HPV.³³ Extragenital LS does not appear to have similar potential for malignant transformation.³⁴

In a prospective Australian cohort of 507 women with LS (mean age, 55.4 years), remission was induced with potent topical corticosteroids.³⁵ Patients who were adherent to a topical regimen did not develop SCC during follow-up. Those who were nonadherent or partially adherent had a 4.7% risk for SCC.³⁵ In a similar prospective study of 83 women in France, the SCC rate was 9.6% in lesions that were untreated or irregularly treated.³⁶ These studies provide essential evidence that appropriately treating LS can prevent SCC at a later date, though longer-term data are lacking.

The rate of SCC arising in male genital LS may approach 8.4%,³⁷ with a lag time of 17 years from onset of LS to SCC diagnosis.³⁸ Although circumcision often is considered curative for male genital LS, patients have been observed to develop penile SCC at least 5 years after circumcision.³⁹ Male penile SCC in a background of LS may not necessarily be HPV associated.⁴⁰

Marjolin Ulcer

Chronic ulcers or scars, typically postburn scars, may undergo malignant transformation, with SCC being the most common carcinoma.⁴¹ Squamous cell carcinoma in the context of a chronic ulcer or wound is known as a Marjolin ulcer (MU). Up to 2% of burn scars have been observed to undergo malignant transformation.⁴² Marjolin ulcers tend to behave aggressively once they form, and it has been proposed that removal of scar tissue may be a preventive therapeutic strategy.⁴³ Cohort studies of MU on the lower extremities have observed lag times of 26.4⁴⁴ and 37.9⁴⁵ years, with both studies also noting relatively high rates of local recurrence.

The pathogenesis of MU appears to be multifactorial. Chronic inflammation and scar formation have been implicated. Chronic inflammation and irritation of lesions at natural creases are thought to increase mitotic activity,⁴¹ and local accumulation of toxin may promote mutagenesis.⁴⁶ Scar formation may create a locally immunoprivileged site, allowing for developing tumors to evade the immune system⁴⁷ and become even more aggressive as the tumor accumulates.⁴⁸ Scar formation also may prevent the ability of immune cells to penetrate the tumor microenvironment and access lymphatic channels.⁴⁹

Hidradenitis Suppurativa

As many as 3.2% of patients with chronic hidradenitis suppurativa (HS) experience malignant transformation to SCC.⁵⁰ Early HS displays subclinical lymphedema in affected sites, which can progress to chronic fibrosis, stasis, and accumulation of protein-rich fluid.⁵¹ Stasis changes have been associated with altered local inflammatory proteins, such as toll-like receptors, β-defensins, and interleukins.⁵²

A retrospective cohort study of 12 patients revealed a lag time of 28.5 years from HS diagnosis to the manifestation of malignancy.⁵³ After local excision, 7 patients developed recurrence, with 100% mortality. Squamous cell carcinomas were well differentiated and moderately differentiated.⁵³ A 2017 literature review of 62 case reports calculated a mean lag time of 27 years. Despite 85% of SCCs being well differentiated and moderately differentiated, nearly half of patients died within 2 years.⁵⁴ As seen in other inflammatory conditions, HPV can complicate perineal HS and promote SCC tumorigenesis.⁵⁵

Squamous cell carcinomas arising within HS lesions are more prevalent in males (6.75:1 ratio),^54,56 despite HS being more prevalent in females (2:1 ratio).⁵⁷ Similar to DLE, SCCs arising in HS are aggressive and are seen more in males, despite both conditions being female predominant. Incidence and mortality rates for primary cutaneous SCC are higher for men vs women⁵⁸; however, the discordance in aggressive behavior seen more commonly in SCC arising from HS or DLE in male patients has yet to be explained.

Malignancy arising within necrobiosis lipoidica diabeticorum (NLD) is rare. A review of 14 published cases noted that 13 were SCC and 1 was leiomyosarcoma.⁵⁹ The lag time was 21.5 years; 31% of cases (N=14) presented with regional lymph node metastasis. Although chronic ulceration is a risk factor for SCC and occurs in as many as one-third of NLD cases, its correlation with ulceration and malignant transformation has not been characterized.

Epidermolysis Bullosa

Recessive dystrophic epidermolysis bullosa (RDEB) is a noninflammatory inherited blistering disease, and patients have an inherently high risk for aggressive SCC.⁶⁰ Other forms of epidermolysis bullosa can lead to SCC, but the rarer RDEB accounts for 69% of SCC cases, with a median age of 36 years at presentation.⁶¹ Although SCCs tend to be well differentiated in RDEB (73.9%),⁶¹ they also exhibit highly aggressive behavior.⁶² In the most severe variant—RDEB-generalized severe—the cumulative risk for SCC-related death in an Australian population was 84.4% at 34 years of age.⁶³

As RDEB is an inherited disorder with potential for malignancy at a young age, the pathogenesis is plausibly different from the previously discussed inflammatory dermatoses. This disease is characterized by a mutation in the collagen VII gene, leading to loss of anchoring fibrils and a basement membrane zone split.⁶⁴ There also can be inherent fibroblast alterations; RDEB fibroblasts create an environment for tumor growth by supporting malignant-cell adhesion and invasion.⁶⁵ Mutations in p53,⁶⁶ local alterations in transforming growth factor β activity,⁶⁷ and downstream matrix metalloproteinase activity⁶⁸ have been implicated.

Additionally, keratinocytes may retain the N-terminal noncollagenous (NC1) domain of truncated collagen VII while losing the anchoring NC2 domain in mutated collagen VII RDEB, thereby supporting anchorless keratinocyte survival and higher metastatic potential.⁶⁹ Retention of this truncated NC1 domain has shown conversion of RDEB keratinocytes to tumor in a xenotransplant mouse model.⁷⁰ A high level of type VII collagen itself may inherently be protumorigenic for keratinocytes.⁷¹

There does not appear to be evidence for HPV involvement in RDEB-associated SCC.⁷² Squamous cell carcinoma development in RDEB appears to be multifactorial,⁷³ but validated tumor models are lacking. Other than conventional oncologic therapy, future directions in the management of RDEB may include gene-, protein- and cell-targeted therapies.⁷³

Conclusion

Squamous cell carcinomas are known to arise within chronic cutaneous inflammatory dermatoses. Tumorigenesis peaks relatively early in new orolabial DLE, LS, and OLP cases, and can occur over many decades in cutaneous DLE, HLP, HS, NLD, and chronic wounds or scars, summarized in the Table. Frequent SCCs are observed in high-risk subtypes of epidermolysis bullosa. Dermatologists must examine areas affected by these diseases at regular intervals, being mindful of the possibility of SCC development. Furthermore, dermatologists should adopt a lower threshold to biopsy suspicious lesions, especially those that develop within relatively new orolabial DLE, chronic HS, or chronic wound cases, as SCC in these settings is particularly aggressive and displays mortality and metastasis rates that exceed those of common cutaneous SCC.


TOPLINE:

Nearly half of the US Food and Drug Administration (FDA) approvals for dermatologic drugs between 2012 and 2022 were considered first in class or first in indication.

METHODOLOGY:

• Only five new drugs for diseases treated mostly by dermatologists were approved by the FDA between 1999 and 2009.
• In a cross-sectional analysis to characterize the frequency and degree of innovation of dermatologic drugs approved more recently, researchers identified new and supplemental dermatologic drugs approved between January 1, 2012, and December 31, 2022, from FDA lists, Centers for Medicare & Medicaid Services CenterWatch, and peer-reviewed articles.
• They used five proxy measures to estimate each drug’s degree of innovation: FDA designation (first in class, advance in class, or addition to class), independent clinical usefulness ratings, and benefit ratings by health technology assessment organizations.

TAKEAWAY:

• The study authors identified 52 new drug applications and 26 supplemental new indications approved by the FDA for dermatologic indications between 2012 and 2022.
• Of the 52 new drugs, the researchers categorized 11 (21%) as first in class and 13 (25%) as first in indication.
• An analysis of benefit ratings available for 38 of the drugs showed that 15 (39%) were rated as being clinically useful or having high added therapeutic benefit.
• Of the 10 supplemental new indications with ratings by any organization, 3 (30%) were rated as clinically useful or having high added therapeutic benefit.

IN PRACTICE:

While innovative drug development in dermatology may have increased, “these findings also highlight opportunities to develop more truly innovative dermatologic agents, particularly for diseases with unmet therapeutic need,” the authors wrote.

SOURCE:

First author Samir Kamat, MD, of the Medical Education Department at Icahn School of Medicine at Mount Sinai, New York City, and corresponding author Ravi Gupta, MD, MSHP, of the Internal Medicine Division at Johns Hopkins University, Baltimore, Maryland, led the research. The study was published online as a research letter on December 20, 2023, in JAMA Dermatology.

LIMITATIONS:

They include the use of individual indications to assess clinical usefulness and benefit ratings. Many drugs, particularly supplemental indications, lacked such ratings. Reformulations of already marketed drugs or indications were not included.

DISCLOSURES:

Dr. Kamat and Dr. Gupta had no relevant disclosures. Three coauthors reported having received financial support outside of the submitted work.

A version of this article appeared on Medscape.com.

TOPLINE:

Nearly half of the US Food and Drug Administration (FDA) approvals for dermatologic drugs between 2012 and 2022 were considered first in class or first in indication.

METHODOLOGY:

• Only five new drugs for diseases treated mostly by dermatologists were approved by the FDA between 1999 and 2009.
• In a cross-sectional analysis to characterize the frequency and degree of innovation of dermatologic drugs approved more recently, researchers identified new and supplemental dermatologic drugs approved between January 1, 2012, and December 31, 2022, from FDA lists, Centers for Medicare & Medicaid Services CenterWatch, and peer-reviewed articles.
• They used five proxy measures to estimate each drug’s degree of innovation: FDA designation (first in class, advance in class, or addition to class), independent clinical usefulness ratings, and benefit ratings by health technology assessment organizations.

TAKEAWAY:

• The study authors identified 52 new drug applications and 26 supplemental new indications approved by the FDA for dermatologic indications between 2012 and 2022.
• Of the 52 new drugs, the researchers categorized 11 (21%) as first in class and 13 (25%) as first in indication.
• An analysis of benefit ratings available for 38 of the drugs showed that 15 (39%) were rated as being clinically useful or having high added therapeutic benefit.
• Of the 10 supplemental new indications with ratings by any organization, 3 (30%) were rated as clinically useful or having high added therapeutic benefit.

IN PRACTICE:

While innovative drug development in dermatology may have increased, “these findings also highlight opportunities to develop more truly innovative dermatologic agents, particularly for diseases with unmet therapeutic need,” the authors wrote.

SOURCE:

First author Samir Kamat, MD, of the Medical Education Department at Icahn School of Medicine at Mount Sinai, New York City, and corresponding author Ravi Gupta, MD, MSHP, of the Internal Medicine Division at Johns Hopkins University, Baltimore, Maryland, led the research. The study was published online as a research letter on December 20, 2023, in JAMA Dermatology.

LIMITATIONS:

They include the use of individual indications to assess clinical usefulness and benefit ratings. Many drugs, particularly supplemental indications, lacked such ratings. Reformulations of already marketed drugs or indications were not included.

DISCLOSURES:

Dr. Kamat and Dr. Gupta had no relevant disclosures. Three coauthors reported having received financial support outside of the submitted work.

A version of this article appeared on Medscape.com.

TOPLINE:

Nearly half of the US Food and Drug Administration (FDA) approvals for dermatologic drugs between 2012 and 2022 were considered first in class or first in indication.

METHODOLOGY:

• Only five new drugs for diseases treated mostly by dermatologists were approved by the FDA between 1999 and 2009.
• In a cross-sectional analysis to characterize the frequency and degree of innovation of dermatologic drugs approved more recently, researchers identified new and supplemental dermatologic drugs approved between January 1, 2012, and December 31, 2022, from FDA lists, Centers for Medicare & Medicaid Services CenterWatch, and peer-reviewed articles.
• They used five proxy measures to estimate each drug’s degree of innovation: FDA designation (first in class, advance in class, or addition to class), independent clinical usefulness ratings, and benefit ratings by health technology assessment organizations.

TAKEAWAY:

• The study authors identified 52 new drug applications and 26 supplemental new indications approved by the FDA for dermatologic indications between 2012 and 2022.
• Of the 52 new drugs, the researchers categorized 11 (21%) as first in class and 13 (25%) as first in indication.
• An analysis of benefit ratings available for 38 of the drugs showed that 15 (39%) were rated as being clinically useful or having high added therapeutic benefit.
• Of the 10 supplemental new indications with ratings by any organization, 3 (30%) were rated as clinically useful or having high added therapeutic benefit.

IN PRACTICE:

While innovative drug development in dermatology may have increased, “these findings also highlight opportunities to develop more truly innovative dermatologic agents, particularly for diseases with unmet therapeutic need,” the authors wrote.

SOURCE:

First author Samir Kamat, MD, of the Medical Education Department at Icahn School of Medicine at Mount Sinai, New York City, and corresponding author Ravi Gupta, MD, MSHP, of the Internal Medicine Division at Johns Hopkins University, Baltimore, Maryland, led the research. The study was published online as a research letter on December 20, 2023, in JAMA Dermatology.

LIMITATIONS:

They include the use of individual indications to assess clinical usefulness and benefit ratings. Many drugs, particularly supplemental indications, lacked such ratings. Reformulations of already marketed drugs or indications were not included.

DISCLOSURES:

Dr. Kamat and Dr. Gupta had no relevant disclosures. Three coauthors reported having received financial support outside of the submitted work.

A version of this article appeared on Medscape.com.

To the Editor:

Treatment of cancer, including cutaneous malignancy, has been transformed by the use of immunotherapeutic agents such as immune checkpoint inhibitors (ICIs) that target cytotoxic T lymphocyte-associated antigen 4, programmed cell-death protein 1 (PD-1), or programmed cell-death ligand 1 (PD-L1). However, these drugs are associated with a distinct set of immune-related adverse events (IRAEs). We present a case of generalized eruptive keratoacanthoma of Grzybowski associated with the ICI cemiplimab.

A 94-year-old White woman presented to the dermatology clinic with acute onset of extensive, locally advanced cutaneous squamous cell carcinoma (cSCC) of the upper right posterolateral calf as well as multiple noninvasive cSCCs of the arms and legs. Her medical history was remarkable for widespread actinic keratoses and numerous cSCCs. The patient had no personal or family history of melanoma. Various cSCCs had required treatment with electrodesiccation and curettage, topical or intralesional 5-fluorouracil, and Mohs micrographic surgery. Approximately 1 year prior to presentation, oral acitretin was initiated to help control the cSCC. Given the extent of locally advanced disease, which was considered unresectable, she was referred to oncology but continued to follow up with dermatology. Positron emission tomography was remarkable for hypermetabolic cutaneous thickening in the upper right posterolateral calf with no evidence of visceral disease.

The patient was started on cemiplimab, an anti-PD-1 monoclonal antibody ICI indicated for the treatment of both metastatic and advanced cSCC. After 4 cycles of intravenous cemiplimab, the patient developed widespread nodules covering the arms and legs (Figure 1) as well as associated tenderness and pruritus. Biopsies of nodules revealed superficially invasive, well-differentiated cSCC consistent with keratoacanthoma. Although a lymphocytic infiltrate was present, no other specific reaction pattern, such as a lichenoid infiltrate, was present (Figure 2).

Positron emission tomography was repeated, demonstrating resolution of the right calf lesion; however, new diffuse cutaneous lesions and inguinal lymph node involvement were present, again without evidence of visceral disease. Given the clinical and histologic findings, a diagnosis of generalized eruptive keratoacanthoma of Grzybowski was made. Cemiplimab was discontinued after the fifth cycle. The patient declined further systemic treatment, instead choosing a regimen of topical steroids and an emollient. 

Immunotherapeutics have transformed cancer therapy, which includes ICIs that target cytotoxic T lymphocyte-associated antigen 4, PD-1, or PD-L1. Increased activity of these checkpoints allows tumor cells to downregulate T-cell activation, thereby evading immune destruction. When PD-1 on T cells binds PD-L1 on tumor cells, T lymphocytes are inhibited from cytotoxic-mediated killing. Therefore, anti-PD-1 ICIs such as cemiplimab permit T-lymphocyte activation and destruction of malignant cells. However, this unique mechanism of immunotherapy is associated with an array of IRAEs, which often manifest in a delayed and prolonged fashion.¹ Immune-related adverse events most commonly affect the gastrointestinal tract as well as the endocrine and dermatologic systems.² Notably, patients with certain tumors who experience these adverse effects might be more likely to have superior overall survival; therefore, IRAEs are sometimes used as an indicator of favorable treatment response.^2,3

Dermatologic IRAEs associated with the use of a PD-1 inhibitor include lichenoid reactions, pruritus, morbilliform eruptions, vitiligo, and bullous pemphigoid.^4,5 Eruptions of keratoacanthoma rarely have been reported following treatment with the PD-1 inhibitors nivolumab and pembrolizumab.^3,6,7 In our patient, we believe the profound and generalized eruptive keratoacanthoma—a well-differentiated cSCC variant—was related to treatment of locally advanced cSCC with cemiplimab. The mechanism underlying the formation of anti-PD-1 eruptive keratoacanthoma is not well understood. In susceptible patients, it is plausible that the inflammatory environment permitted by ICIs paradoxically induces regression of tumors such as locally invasive cSCC and simultaneously promotes formation of keratoacanthoma.

The role of inflammation in the pathogenesis and progression of cSCC is complex and possibly involves contrasting roles of leukocyte subpopulations.⁸ The increased incidence of cSCC in the immunocompromised population,⁸ PD-L1 overexpression in cSCC,^9,10 and successful treatment of cSCC with PD-1 inhibition¹⁰ all suggest that inhibition of specific inflammatory pathways is pivotal in tumor pathogenesis. However, increased inflammation, particularly inflammation driven by T lymphocytes and Langerhans cells, also is believed to play a key role in the formation of cSCCs, including the degeneration of actinic keratosis into cSCC. Moreover, because keratoacanthomas are believed to be a cSCC variant and also are associated with PD-L1 overexpression,⁹ it is perplexing that PD-1 blockade may result in eruptive keratoacanthoma in some patients while also treating locally advanced cSCC, as seen in our patient. Successful treatment of keratoacanthoma with anti-inflammatory intralesional or topical corticosteroids adds to this complicated picture.³

We hypothesize that the pathogenesis of invasive cSCC and keratoacanthoma shares certain immune-mediated mechanisms but also differs in distinct manners. To understand the relationship between systemic treatment of cSCC and eruptive keratoacanthoma, further research is required.

In addition, the RAS/BRAF/MEK oncogenic pathway may be involved in the development of cSCCs associated with anti-PD-1. It is hypothesized that BRAF and MEK inhibition increases T-cell infiltration and increases PD-L1 expression on tumor cells,¹¹ thus increasing the susceptibility of those cells to PD-1 blockade. Further supporting a relationship between the RAS/BRAF/MEK and PD-1 pathways, BRAF inhibitors are associated with development of SCCs and verrucal keratosis by upregulation of the RAS pathway.^12,13 Perhaps a common mechanism underlying these pathways results in their shared association for an increased risk for cSCC upon blockade. More research is needed to fully elucidate the underlying biochemical mechanism of immunotherapy and formation of SCCs, such as keratoacanthoma. 

Treatment of solitary keratoacanthoma often involves surgical excision; however, the sheer number of lesions in eruptive keratoacanthoma presents a larger dilemma. Because oral systemic retinoids have been shown to be most effective for treating eruptive keratoacanthoma, they are considered first-line therapy as monotherapy or in combination with surgical excision.³ Other treatment options include intralesional or topical corticosteroids, cyclosporine, 5-fluorouracil, imiquimod, and cryotherapy.^3,6

The development of ICIs has revolutionized the treatment of cutaneous malignancy, yet we have a great deal more to comprehend on the systemic effects of these medications. Although IRAEs may signal a better response to therapy, some of these effects regrettably can be dose limiting. In our patient, cemiplimab was successful in treating locally advanced cSCC, but treatment also resulted in devastating widespread eruptive keratoacanthoma. The mechanism of this kind of eruption has yet to be understood; we hypothesize that it likely involves T lymphocyte–driven inflammation and the interplay of molecular and immune-mediated pathways.

To the Editor:

Treatment of cancer, including cutaneous malignancy, has been transformed by the use of immunotherapeutic agents such as immune checkpoint inhibitors (ICIs) that target cytotoxic T lymphocyte-associated antigen 4, programmed cell-death protein 1 (PD-1), or programmed cell-death ligand 1 (PD-L1). However, these drugs are associated with a distinct set of immune-related adverse events (IRAEs). We present a case of generalized eruptive keratoacanthoma of Grzybowski associated with the ICI cemiplimab.

A 94-year-old White woman presented to the dermatology clinic with acute onset of extensive, locally advanced cutaneous squamous cell carcinoma (cSCC) of the upper right posterolateral calf as well as multiple noninvasive cSCCs of the arms and legs. Her medical history was remarkable for widespread actinic keratoses and numerous cSCCs. The patient had no personal or family history of melanoma. Various cSCCs had required treatment with electrodesiccation and curettage, topical or intralesional 5-fluorouracil, and Mohs micrographic surgery. Approximately 1 year prior to presentation, oral acitretin was initiated to help control the cSCC. Given the extent of locally advanced disease, which was considered unresectable, she was referred to oncology but continued to follow up with dermatology. Positron emission tomography was remarkable for hypermetabolic cutaneous thickening in the upper right posterolateral calf with no evidence of visceral disease.

The patient was started on cemiplimab, an anti-PD-1 monoclonal antibody ICI indicated for the treatment of both metastatic and advanced cSCC. After 4 cycles of intravenous cemiplimab, the patient developed widespread nodules covering the arms and legs (Figure 1) as well as associated tenderness and pruritus. Biopsies of nodules revealed superficially invasive, well-differentiated cSCC consistent with keratoacanthoma. Although a lymphocytic infiltrate was present, no other specific reaction pattern, such as a lichenoid infiltrate, was present (Figure 2).

Positron emission tomography was repeated, demonstrating resolution of the right calf lesion; however, new diffuse cutaneous lesions and inguinal lymph node involvement were present, again without evidence of visceral disease. Given the clinical and histologic findings, a diagnosis of generalized eruptive keratoacanthoma of Grzybowski was made. Cemiplimab was discontinued after the fifth cycle. The patient declined further systemic treatment, instead choosing a regimen of topical steroids and an emollient. 

Immunotherapeutics have transformed cancer therapy, which includes ICIs that target cytotoxic T lymphocyte-associated antigen 4, PD-1, or PD-L1. Increased activity of these checkpoints allows tumor cells to downregulate T-cell activation, thereby evading immune destruction. When PD-1 on T cells binds PD-L1 on tumor cells, T lymphocytes are inhibited from cytotoxic-mediated killing. Therefore, anti-PD-1 ICIs such as cemiplimab permit T-lymphocyte activation and destruction of malignant cells. However, this unique mechanism of immunotherapy is associated with an array of IRAEs, which often manifest in a delayed and prolonged fashion.¹ Immune-related adverse events most commonly affect the gastrointestinal tract as well as the endocrine and dermatologic systems.² Notably, patients with certain tumors who experience these adverse effects might be more likely to have superior overall survival; therefore, IRAEs are sometimes used as an indicator of favorable treatment response.^2,3

Dermatologic IRAEs associated with the use of a PD-1 inhibitor include lichenoid reactions, pruritus, morbilliform eruptions, vitiligo, and bullous pemphigoid.^4,5 Eruptions of keratoacanthoma rarely have been reported following treatment with the PD-1 inhibitors nivolumab and pembrolizumab.^3,6,7 In our patient, we believe the profound and generalized eruptive keratoacanthoma—a well-differentiated cSCC variant—was related to treatment of locally advanced cSCC with cemiplimab. The mechanism underlying the formation of anti-PD-1 eruptive keratoacanthoma is not well understood. In susceptible patients, it is plausible that the inflammatory environment permitted by ICIs paradoxically induces regression of tumors such as locally invasive cSCC and simultaneously promotes formation of keratoacanthoma.

The role of inflammation in the pathogenesis and progression of cSCC is complex and possibly involves contrasting roles of leukocyte subpopulations.⁸ The increased incidence of cSCC in the immunocompromised population,⁸ PD-L1 overexpression in cSCC,^9,10 and successful treatment of cSCC with PD-1 inhibition¹⁰ all suggest that inhibition of specific inflammatory pathways is pivotal in tumor pathogenesis. However, increased inflammation, particularly inflammation driven by T lymphocytes and Langerhans cells, also is believed to play a key role in the formation of cSCCs, including the degeneration of actinic keratosis into cSCC. Moreover, because keratoacanthomas are believed to be a cSCC variant and also are associated with PD-L1 overexpression,⁹ it is perplexing that PD-1 blockade may result in eruptive keratoacanthoma in some patients while also treating locally advanced cSCC, as seen in our patient. Successful treatment of keratoacanthoma with anti-inflammatory intralesional or topical corticosteroids adds to this complicated picture.³

We hypothesize that the pathogenesis of invasive cSCC and keratoacanthoma shares certain immune-mediated mechanisms but also differs in distinct manners. To understand the relationship between systemic treatment of cSCC and eruptive keratoacanthoma, further research is required.

In addition, the RAS/BRAF/MEK oncogenic pathway may be involved in the development of cSCCs associated with anti-PD-1. It is hypothesized that BRAF and MEK inhibition increases T-cell infiltration and increases PD-L1 expression on tumor cells,¹¹ thus increasing the susceptibility of those cells to PD-1 blockade. Further supporting a relationship between the RAS/BRAF/MEK and PD-1 pathways, BRAF inhibitors are associated with development of SCCs and verrucal keratosis by upregulation of the RAS pathway.^12,13 Perhaps a common mechanism underlying these pathways results in their shared association for an increased risk for cSCC upon blockade. More research is needed to fully elucidate the underlying biochemical mechanism of immunotherapy and formation of SCCs, such as keratoacanthoma. 

Treatment of solitary keratoacanthoma often involves surgical excision; however, the sheer number of lesions in eruptive keratoacanthoma presents a larger dilemma. Because oral systemic retinoids have been shown to be most effective for treating eruptive keratoacanthoma, they are considered first-line therapy as monotherapy or in combination with surgical excision.³ Other treatment options include intralesional or topical corticosteroids, cyclosporine, 5-fluorouracil, imiquimod, and cryotherapy.^3,6

The development of ICIs has revolutionized the treatment of cutaneous malignancy, yet we have a great deal more to comprehend on the systemic effects of these medications. Although IRAEs may signal a better response to therapy, some of these effects regrettably can be dose limiting. In our patient, cemiplimab was successful in treating locally advanced cSCC, but treatment also resulted in devastating widespread eruptive keratoacanthoma. The mechanism of this kind of eruption has yet to be understood; we hypothesize that it likely involves T lymphocyte–driven inflammation and the interplay of molecular and immune-mediated pathways.

To the Editor:

Treatment of cancer, including cutaneous malignancy, has been transformed by the use of immunotherapeutic agents such as immune checkpoint inhibitors (ICIs) that target cytotoxic T lymphocyte-associated antigen 4, programmed cell-death protein 1 (PD-1), or programmed cell-death ligand 1 (PD-L1). However, these drugs are associated with a distinct set of immune-related adverse events (IRAEs). We present a case of generalized eruptive keratoacanthoma of Grzybowski associated with the ICI cemiplimab.

A 94-year-old White woman presented to the dermatology clinic with acute onset of extensive, locally advanced cutaneous squamous cell carcinoma (cSCC) of the upper right posterolateral calf as well as multiple noninvasive cSCCs of the arms and legs. Her medical history was remarkable for widespread actinic keratoses and numerous cSCCs. The patient had no personal or family history of melanoma. Various cSCCs had required treatment with electrodesiccation and curettage, topical or intralesional 5-fluorouracil, and Mohs micrographic surgery. Approximately 1 year prior to presentation, oral acitretin was initiated to help control the cSCC. Given the extent of locally advanced disease, which was considered unresectable, she was referred to oncology but continued to follow up with dermatology. Positron emission tomography was remarkable for hypermetabolic cutaneous thickening in the upper right posterolateral calf with no evidence of visceral disease.

The patient was started on cemiplimab, an anti-PD-1 monoclonal antibody ICI indicated for the treatment of both metastatic and advanced cSCC. After 4 cycles of intravenous cemiplimab, the patient developed widespread nodules covering the arms and legs (Figure 1) as well as associated tenderness and pruritus. Biopsies of nodules revealed superficially invasive, well-differentiated cSCC consistent with keratoacanthoma. Although a lymphocytic infiltrate was present, no other specific reaction pattern, such as a lichenoid infiltrate, was present (Figure 2).

Positron emission tomography was repeated, demonstrating resolution of the right calf lesion; however, new diffuse cutaneous lesions and inguinal lymph node involvement were present, again without evidence of visceral disease. Given the clinical and histologic findings, a diagnosis of generalized eruptive keratoacanthoma of Grzybowski was made. Cemiplimab was discontinued after the fifth cycle. The patient declined further systemic treatment, instead choosing a regimen of topical steroids and an emollient. 

Immunotherapeutics have transformed cancer therapy, which includes ICIs that target cytotoxic T lymphocyte-associated antigen 4, PD-1, or PD-L1. Increased activity of these checkpoints allows tumor cells to downregulate T-cell activation, thereby evading immune destruction. When PD-1 on T cells binds PD-L1 on tumor cells, T lymphocytes are inhibited from cytotoxic-mediated killing. Therefore, anti-PD-1 ICIs such as cemiplimab permit T-lymphocyte activation and destruction of malignant cells. However, this unique mechanism of immunotherapy is associated with an array of IRAEs, which often manifest in a delayed and prolonged fashion.¹ Immune-related adverse events most commonly affect the gastrointestinal tract as well as the endocrine and dermatologic systems.² Notably, patients with certain tumors who experience these adverse effects might be more likely to have superior overall survival; therefore, IRAEs are sometimes used as an indicator of favorable treatment response.^2,3

Dermatologic IRAEs associated with the use of a PD-1 inhibitor include lichenoid reactions, pruritus, morbilliform eruptions, vitiligo, and bullous pemphigoid.^4,5 Eruptions of keratoacanthoma rarely have been reported following treatment with the PD-1 inhibitors nivolumab and pembrolizumab.^3,6,7 In our patient, we believe the profound and generalized eruptive keratoacanthoma—a well-differentiated cSCC variant—was related to treatment of locally advanced cSCC with cemiplimab. The mechanism underlying the formation of anti-PD-1 eruptive keratoacanthoma is not well understood. In susceptible patients, it is plausible that the inflammatory environment permitted by ICIs paradoxically induces regression of tumors such as locally invasive cSCC and simultaneously promotes formation of keratoacanthoma.

The role of inflammation in the pathogenesis and progression of cSCC is complex and possibly involves contrasting roles of leukocyte subpopulations.⁸ The increased incidence of cSCC in the immunocompromised population,⁸ PD-L1 overexpression in cSCC,^9,10 and successful treatment of cSCC with PD-1 inhibition¹⁰ all suggest that inhibition of specific inflammatory pathways is pivotal in tumor pathogenesis. However, increased inflammation, particularly inflammation driven by T lymphocytes and Langerhans cells, also is believed to play a key role in the formation of cSCCs, including the degeneration of actinic keratosis into cSCC. Moreover, because keratoacanthomas are believed to be a cSCC variant and also are associated with PD-L1 overexpression,⁹ it is perplexing that PD-1 blockade may result in eruptive keratoacanthoma in some patients while also treating locally advanced cSCC, as seen in our patient. Successful treatment of keratoacanthoma with anti-inflammatory intralesional or topical corticosteroids adds to this complicated picture.³

We hypothesize that the pathogenesis of invasive cSCC and keratoacanthoma shares certain immune-mediated mechanisms but also differs in distinct manners. To understand the relationship between systemic treatment of cSCC and eruptive keratoacanthoma, further research is required.

In addition, the RAS/BRAF/MEK oncogenic pathway may be involved in the development of cSCCs associated with anti-PD-1. It is hypothesized that BRAF and MEK inhibition increases T-cell infiltration and increases PD-L1 expression on tumor cells,¹¹ thus increasing the susceptibility of those cells to PD-1 blockade. Further supporting a relationship between the RAS/BRAF/MEK and PD-1 pathways, BRAF inhibitors are associated with development of SCCs and verrucal keratosis by upregulation of the RAS pathway.^12,13 Perhaps a common mechanism underlying these pathways results in their shared association for an increased risk for cSCC upon blockade. More research is needed to fully elucidate the underlying biochemical mechanism of immunotherapy and formation of SCCs, such as keratoacanthoma. 

Treatment of solitary keratoacanthoma often involves surgical excision; however, the sheer number of lesions in eruptive keratoacanthoma presents a larger dilemma. Because oral systemic retinoids have been shown to be most effective for treating eruptive keratoacanthoma, they are considered first-line therapy as monotherapy or in combination with surgical excision.³ Other treatment options include intralesional or topical corticosteroids, cyclosporine, 5-fluorouracil, imiquimod, and cryotherapy.^3,6

The development of ICIs has revolutionized the treatment of cutaneous malignancy, yet we have a great deal more to comprehend on the systemic effects of these medications. Although IRAEs may signal a better response to therapy, some of these effects regrettably can be dose limiting. In our patient, cemiplimab was successful in treating locally advanced cSCC, but treatment also resulted in devastating widespread eruptive keratoacanthoma. The mechanism of this kind of eruption has yet to be understood; we hypothesize that it likely involves T lymphocyte–driven inflammation and the interplay of molecular and immune-mediated pathways.

Toluidine blue (TB), a dye with metachromatic staining properties, was developed in 1856 by William Henry Perkin.¹ Metachromasia is a perceptible change in the color of staining of living tissue due to the electrochemical properties of the tissue. Tissues that contain high concentrations of ionized sulfate and phosphate groups (high concentrations of free electronegative groups) form polymeric aggregates of the basic dye solution that alter the absorbed wavelengths of light.² The function of this characteristic is to use a single dye to highlight different structures in tissue based on their relative chemical differences.³

Toluidine blue primarily was used within the dye industry until the 1960s, when it was first used in vital staining of the oral mucosa.² Because of the tissue absorption potential, this technique was used to detect the location of oral malignancies.⁴ Since then, TB has progressively been used for staining fresh frozen sections in Mohs micrographic surgery (MMS). In a 2003 survey study (N=310), 16.8% of surgeons performing MMS reported using TB in their laboratory.⁵ We sought to systematically review the published literature describing the uses of TB in the setting of fresh frozen sections and MMS.

Methods

We conducted a systematic search of the PubMed and Cochrane databases for articles published before December 1, 2019, to identify any relevant studies in English. Electronic searches were performed using the terms toluidine blue and Mohs or Mohs micrographic surgery. We manually checked the bibliographies of the identified articles to further identify eligible studies.

Eligibility Criteria—The inclusion criteria were articles that (1) considered TB in the context of MMS, (2) were published in peer-reviewed journals, (3) were published in English, and (4) were available as full text. Systematic reviews were excluded.

Data Extraction and Outcomes—All relevant information regarding the study characteristics, including design, level of evidence, methodologic quality of evidence, pathology examined, and outcome measures, were collected by 2 independent reviewers (T.L. and A.D.) using a predetermined data sheet. The same 2 reviewers were used for all steps of the review process, data were independently obtained, and any discrepancy was introduced for a third opinion (D.H.) and agreed upon by the majority.

Quality Assessment—The level of evidence was evaluated based on the criteria of the Oxford Centre for Evidence-Based Medicine. Two reviewers (T.L. and A.D.) graded each article included in the review.

Results

A total of 25 articles were reviewed. After the titles and abstracts were screened for relevance, 12 articles remained (Figure 1). Of these, 1 compared basal cell carcinoma (BCC) and squamous cell carcinoma (SCC), 4 were related to BCC, 3 were related to SCC, 1 was related to microcystic adnexal carcinoma (MAC), 1 was related to primary cutaneous adenoid cystic carcinoma (PCACC), and 2 were related to technical aspects of the staining process (Table 1).

A majority of the articles included in this review were qualitative and observational in nature, describing the staining characteristics of TB. Study characteristics are summarized in Table 1.

Comment

Basal Cell Carcinoma—Toluidine blue staining characteristics help to identify BCC nests by differentiating them from hair follicles in frozen sections. The metachromatic characteristic of TB stains the inner root sheath deep blue and highlights the surrounding stromal mucin of BCC a magenta color.^18,19 In hematoxylin and eosin (H&E) stains, these 2 distinct structures can be differentiated by cleft formation around tumor nests, mitotic figures, and the lack of a fibrous sheath present in BCC tumors.²⁰ The advantages and limitations of TB staining of BCC are presented in Table 2.

Humphreys et al⁶ suggested a noticeable difference between H&E and TB in the staining of cellular and stromal components. The nuclear detail of tumor cells was subjectively sharper and clearer with TB staining. The staining of stromal components may provide the most assistance in locating BCC islands. Mucopolysaccharide staining may be absent in H&E but stain a deep magenta with TB. Although the presence of mucopolysaccharides does not specifically indicate a tumor, it may prompt further attention and provide an indicator for sparse and infiltrative tumor cells.⁶ The metachromatic stromal change may indicate a narrow tumor-free margin where additional deeper sections often reveal tumor that may warrant additional resection margin in more aggressive malignancies. In particular, sclerosing/morpheaform BCCs have been shown to induce glycosaminoglycan synthesis and are highlighted more readily with TB than with H&E when compared to surrounding tissue.²¹ This differentiation in staining has remained a popular reason to routinely incorporate TB into the staining of infiltrative and morpheaform variants of BCC. Additionally, stromal mast cells are believed to be more abundant in the stroma of BCC and are more readily visualized in tissue specimens stained with TB, appearing as bright purple metachromatic granules. These granules are larger than normal and are increased in number.⁶

The margin behavior of BCC stained with TB was further characterized by Goldberg et al,⁸ who coined the term setting sun sign, which may be present in sequential sections of a disappearing nodule of a BCC tumor. Stroma, inflammatory infiltrate, and mast cells produce a magenta glow surrounding BCC tumors that is reminiscent of a setting sun (Figure 2). Invasive BCC is considered variable in this presentation, primarily because of zones of cell-free fluid and edema or the second area of inflammatory cells. This unique sign may benefit the inspecting Mohs surgeon by providing a clue to an underlying process that may have residual BCC tumors. The setting sun sign also may assist in identifying exact surgical margins.⁸

The nasal surface has a predilection for BCC.²² The skin of the nose has numerous look-alike structures to consider for complete tumor removal and avoidance of unnecessary removal. One challenge is distinguishing follicular basaloid proliferations (FBP) from BCC, a scenario that is more common on the nose.²² When TB staining was used, the sensitivity for detecting FBP reached 100% in 34 cases reviewed by Donaldson and Weber.¹⁰ None of the cases examined showed TB metachromasia surrounding FBP, thus indicating that TB can dependably identify this benign entity. Conversely, 5% (N=279) of BCCs confirmed on H&E did not exhibit surrounding TB metachromasia. This finding is concerning regarding the specificity of TB staining for BCC, but the authors of this study suggested the possibility that these exceptions were benign “simulants” (ie, trichoepithelioma) of BCC.¹⁰

The use of TB also has been shown to be statistically beneficial in Mohs training. In a single-center, single-fellow experiment, the sensitivity and specificity of using TB for BCC were extrapolated.⁹ Using TB as an adjunct in deep sections showed superior sensitivity to H&E alone in identifying BCC, increasing sensitivity from 96.3% to 99.7%. In a cohort of 352 BCC excisions and frozen sections, only 1 BCC was not completely excised. If H&E only had been performed, the fellow would have missed 13 residual BCC tumors.⁹

Bennett and Taher⁷ described a case in which hyaluronic acid (HA) from a filler injection was confused with the HA surrounding BCC tumor nests. They found that when TB is used as an adjunct, the HA filler is easier to differentiate from the HA surrounding the BCC tumor nests. In frozen sections stained with TB, the HA filler appeared as an amorphous, metachromatic, reddish-purple, whereas the HA surrounding the BCC tumor nests appeared as a well-defined red. These findings were less obvious in the same sections stained with H&E alone.⁷

Squamous Cell Carcinoma—In early investigations, the utility of TB in identifying SCC in frozen sections was thought to be limited. The description by Humphreys and colleagues⁶ of staining characteristics in SCC suggested that the nuclear detail that H&E provides is more easily recognized. The deep aqua nuclear staining produced with TB was considered more difficult to observe than the cytoplasmic eosinophilia of pyknotic and keratinizing cells in H&E.⁶

Toluidine blue may be beneficial in providing unique staining characteristics to further detail tumors that are difficult to interpret, such as spindle cell SCC and perineural invasion of aggressive SCC. In H&E, squamous cells of spindle cell SCC (scSCC) blend into the background of inflammatory cells and can be perceptibly difficult to locate. A small cohort of 3 Mohs surgeons who routinely use H&E were surveyed on their ability to detect a proven scSCC in H&E or TB by photograph.¹² All 3 were able to detect the scSCC in the TB photographs, but only 2 of 3 were able to detect it in H&E photographs. All 3 surgeons agreed that TB was preferable to H&E for this tumor type. These findings suggested that TB may be superior and preferred over H&E for visualizing tumor cells of scSCC.¹² The TB staining characteristics of perineural invasion of aggressive SCC have been referred to as the perineural corona sign because of the bright magenta stain that forms around affected nerves.¹³ Drosou et al¹³ suggested that TB may enhance the diagnostic accuracy for perineural SCC.

Rare Tumors—The adjunctive use of TB with H&E has been examined in rare tumors. Published reports have highlighted its use in MMS for treating MAC and PCACC. Toluidine blue exhibits staining advantages for these tumors. It may render isolated nests and perineural invasion of MAC more easily visible on frozen section.¹⁵

Although PCACC is rare, the recurrence rate is high.²³ Toluidine blue has been used with MMS to ensure complete removal and higher cure rates. The metachromatic nature of TB is advantageous in staining the HA present in these tumors. Those who have reported the use of TB for PCACC prefer it to H&E for frozen sections.¹⁴

Technical Aspects—The staining time for TB-treated slides is reduced compared to H&E staining; staining can be efficiently done in frozen sections in less than 2.5 minutes using the method shown in Table 3.¹⁷ In comparison, typical H&E staining takes 9 minutes, and older TB techniques take 7 minutes.⁶

Conclusion

Toluidine blue may play an important and helpful role in the successful diagnosis and treatment of particular cutaneous tumors by providing additional diagnostic information. Although surgeons performing MMS will continue using the staining protocols with which they are most comfortable, adjunctive use of TB over time may provide an additional benefit at low risk for disrupting practice efficiency or workflow. Many Mohs surgeons are accustomed to using this stain, even preferring to interpret only TB-stained slides for cutaneous malignancy. Most published studies on this topic have been observational in nature, and additional controlled trials may be warranted to determine the effects on outcomes in real-world practice.

Toluidine blue (TB), a dye with metachromatic staining properties, was developed in 1856 by William Henry Perkin.¹ Metachromasia is a perceptible change in the color of staining of living tissue due to the electrochemical properties of the tissue. Tissues that contain high concentrations of ionized sulfate and phosphate groups (high concentrations of free electronegative groups) form polymeric aggregates of the basic dye solution that alter the absorbed wavelengths of light.² The function of this characteristic is to use a single dye to highlight different structures in tissue based on their relative chemical differences.³

Toluidine blue primarily was used within the dye industry until the 1960s, when it was first used in vital staining of the oral mucosa.² Because of the tissue absorption potential, this technique was used to detect the location of oral malignancies.⁴ Since then, TB has progressively been used for staining fresh frozen sections in Mohs micrographic surgery (MMS). In a 2003 survey study (N=310), 16.8% of surgeons performing MMS reported using TB in their laboratory.⁵ We sought to systematically review the published literature describing the uses of TB in the setting of fresh frozen sections and MMS.

Methods

We conducted a systematic search of the PubMed and Cochrane databases for articles published before December 1, 2019, to identify any relevant studies in English. Electronic searches were performed using the terms toluidine blue and Mohs or Mohs micrographic surgery. We manually checked the bibliographies of the identified articles to further identify eligible studies.

Eligibility Criteria—The inclusion criteria were articles that (1) considered TB in the context of MMS, (2) were published in peer-reviewed journals, (3) were published in English, and (4) were available as full text. Systematic reviews were excluded.

Data Extraction and Outcomes—All relevant information regarding the study characteristics, including design, level of evidence, methodologic quality of evidence, pathology examined, and outcome measures, were collected by 2 independent reviewers (T.L. and A.D.) using a predetermined data sheet. The same 2 reviewers were used for all steps of the review process, data were independently obtained, and any discrepancy was introduced for a third opinion (D.H.) and agreed upon by the majority.

Quality Assessment—The level of evidence was evaluated based on the criteria of the Oxford Centre for Evidence-Based Medicine. Two reviewers (T.L. and A.D.) graded each article included in the review.

Results

A total of 25 articles were reviewed. After the titles and abstracts were screened for relevance, 12 articles remained (Figure 1). Of these, 1 compared basal cell carcinoma (BCC) and squamous cell carcinoma (SCC), 4 were related to BCC, 3 were related to SCC, 1 was related to microcystic adnexal carcinoma (MAC), 1 was related to primary cutaneous adenoid cystic carcinoma (PCACC), and 2 were related to technical aspects of the staining process (Table 1).

A majority of the articles included in this review were qualitative and observational in nature, describing the staining characteristics of TB. Study characteristics are summarized in Table 1.

Comment

Basal Cell Carcinoma—Toluidine blue staining characteristics help to identify BCC nests by differentiating them from hair follicles in frozen sections. The metachromatic characteristic of TB stains the inner root sheath deep blue and highlights the surrounding stromal mucin of BCC a magenta color.^18,19 In hematoxylin and eosin (H&E) stains, these 2 distinct structures can be differentiated by cleft formation around tumor nests, mitotic figures, and the lack of a fibrous sheath present in BCC tumors.²⁰ The advantages and limitations of TB staining of BCC are presented in Table 2.

Humphreys et al⁶ suggested a noticeable difference between H&E and TB in the staining of cellular and stromal components. The nuclear detail of tumor cells was subjectively sharper and clearer with TB staining. The staining of stromal components may provide the most assistance in locating BCC islands. Mucopolysaccharide staining may be absent in H&E but stain a deep magenta with TB. Although the presence of mucopolysaccharides does not specifically indicate a tumor, it may prompt further attention and provide an indicator for sparse and infiltrative tumor cells.⁶ The metachromatic stromal change may indicate a narrow tumor-free margin where additional deeper sections often reveal tumor that may warrant additional resection margin in more aggressive malignancies. In particular, sclerosing/morpheaform BCCs have been shown to induce glycosaminoglycan synthesis and are highlighted more readily with TB than with H&E when compared to surrounding tissue.²¹ This differentiation in staining has remained a popular reason to routinely incorporate TB into the staining of infiltrative and morpheaform variants of BCC. Additionally, stromal mast cells are believed to be more abundant in the stroma of BCC and are more readily visualized in tissue specimens stained with TB, appearing as bright purple metachromatic granules. These granules are larger than normal and are increased in number.⁶

The margin behavior of BCC stained with TB was further characterized by Goldberg et al,⁸ who coined the term setting sun sign, which may be present in sequential sections of a disappearing nodule of a BCC tumor. Stroma, inflammatory infiltrate, and mast cells produce a magenta glow surrounding BCC tumors that is reminiscent of a setting sun (Figure 2). Invasive BCC is considered variable in this presentation, primarily because of zones of cell-free fluid and edema or the second area of inflammatory cells. This unique sign may benefit the inspecting Mohs surgeon by providing a clue to an underlying process that may have residual BCC tumors. The setting sun sign also may assist in identifying exact surgical margins.⁸

The nasal surface has a predilection for BCC.²² The skin of the nose has numerous look-alike structures to consider for complete tumor removal and avoidance of unnecessary removal. One challenge is distinguishing follicular basaloid proliferations (FBP) from BCC, a scenario that is more common on the nose.²² When TB staining was used, the sensitivity for detecting FBP reached 100% in 34 cases reviewed by Donaldson and Weber.¹⁰ None of the cases examined showed TB metachromasia surrounding FBP, thus indicating that TB can dependably identify this benign entity. Conversely, 5% (N=279) of BCCs confirmed on H&E did not exhibit surrounding TB metachromasia. This finding is concerning regarding the specificity of TB staining for BCC, but the authors of this study suggested the possibility that these exceptions were benign “simulants” (ie, trichoepithelioma) of BCC.¹⁰

The use of TB also has been shown to be statistically beneficial in Mohs training. In a single-center, single-fellow experiment, the sensitivity and specificity of using TB for BCC were extrapolated.⁹ Using TB as an adjunct in deep sections showed superior sensitivity to H&E alone in identifying BCC, increasing sensitivity from 96.3% to 99.7%. In a cohort of 352 BCC excisions and frozen sections, only 1 BCC was not completely excised. If H&E only had been performed, the fellow would have missed 13 residual BCC tumors.⁹

Bennett and Taher⁷ described a case in which hyaluronic acid (HA) from a filler injection was confused with the HA surrounding BCC tumor nests. They found that when TB is used as an adjunct, the HA filler is easier to differentiate from the HA surrounding the BCC tumor nests. In frozen sections stained with TB, the HA filler appeared as an amorphous, metachromatic, reddish-purple, whereas the HA surrounding the BCC tumor nests appeared as a well-defined red. These findings were less obvious in the same sections stained with H&E alone.⁷

Squamous Cell Carcinoma—In early investigations, the utility of TB in identifying SCC in frozen sections was thought to be limited. The description by Humphreys and colleagues⁶ of staining characteristics in SCC suggested that the nuclear detail that H&E provides is more easily recognized. The deep aqua nuclear staining produced with TB was considered more difficult to observe than the cytoplasmic eosinophilia of pyknotic and keratinizing cells in H&E.⁶

Toluidine blue may be beneficial in providing unique staining characteristics to further detail tumors that are difficult to interpret, such as spindle cell SCC and perineural invasion of aggressive SCC. In H&E, squamous cells of spindle cell SCC (scSCC) blend into the background of inflammatory cells and can be perceptibly difficult to locate. A small cohort of 3 Mohs surgeons who routinely use H&E were surveyed on their ability to detect a proven scSCC in H&E or TB by photograph.¹² All 3 were able to detect the scSCC in the TB photographs, but only 2 of 3 were able to detect it in H&E photographs. All 3 surgeons agreed that TB was preferable to H&E for this tumor type. These findings suggested that TB may be superior and preferred over H&E for visualizing tumor cells of scSCC.¹² The TB staining characteristics of perineural invasion of aggressive SCC have been referred to as the perineural corona sign because of the bright magenta stain that forms around affected nerves.¹³ Drosou et al¹³ suggested that TB may enhance the diagnostic accuracy for perineural SCC.

Rare Tumors—The adjunctive use of TB with H&E has been examined in rare tumors. Published reports have highlighted its use in MMS for treating MAC and PCACC. Toluidine blue exhibits staining advantages for these tumors. It may render isolated nests and perineural invasion of MAC more easily visible on frozen section.¹⁵

Although PCACC is rare, the recurrence rate is high.²³ Toluidine blue has been used with MMS to ensure complete removal and higher cure rates. The metachromatic nature of TB is advantageous in staining the HA present in these tumors. Those who have reported the use of TB for PCACC prefer it to H&E for frozen sections.¹⁴

Technical Aspects—The staining time for TB-treated slides is reduced compared to H&E staining; staining can be efficiently done in frozen sections in less than 2.5 minutes using the method shown in Table 3.¹⁷ In comparison, typical H&E staining takes 9 minutes, and older TB techniques take 7 minutes.⁶

Conclusion

Toluidine blue may play an important and helpful role in the successful diagnosis and treatment of particular cutaneous tumors by providing additional diagnostic information. Although surgeons performing MMS will continue using the staining protocols with which they are most comfortable, adjunctive use of TB over time may provide an additional benefit at low risk for disrupting practice efficiency or workflow. Many Mohs surgeons are accustomed to using this stain, even preferring to interpret only TB-stained slides for cutaneous malignancy. Most published studies on this topic have been observational in nature, and additional controlled trials may be warranted to determine the effects on outcomes in real-world practice.

Toluidine blue (TB), a dye with metachromatic staining properties, was developed in 1856 by William Henry Perkin.¹ Metachromasia is a perceptible change in the color of staining of living tissue due to the electrochemical properties of the tissue. Tissues that contain high concentrations of ionized sulfate and phosphate groups (high concentrations of free electronegative groups) form polymeric aggregates of the basic dye solution that alter the absorbed wavelengths of light.² The function of this characteristic is to use a single dye to highlight different structures in tissue based on their relative chemical differences.³

Toluidine blue primarily was used within the dye industry until the 1960s, when it was first used in vital staining of the oral mucosa.² Because of the tissue absorption potential, this technique was used to detect the location of oral malignancies.⁴ Since then, TB has progressively been used for staining fresh frozen sections in Mohs micrographic surgery (MMS). In a 2003 survey study (N=310), 16.8% of surgeons performing MMS reported using TB in their laboratory.⁵ We sought to systematically review the published literature describing the uses of TB in the setting of fresh frozen sections and MMS.

Methods

We conducted a systematic search of the PubMed and Cochrane databases for articles published before December 1, 2019, to identify any relevant studies in English. Electronic searches were performed using the terms toluidine blue and Mohs or Mohs micrographic surgery. We manually checked the bibliographies of the identified articles to further identify eligible studies.

Eligibility Criteria—The inclusion criteria were articles that (1) considered TB in the context of MMS, (2) were published in peer-reviewed journals, (3) were published in English, and (4) were available as full text. Systematic reviews were excluded.

Data Extraction and Outcomes—All relevant information regarding the study characteristics, including design, level of evidence, methodologic quality of evidence, pathology examined, and outcome measures, were collected by 2 independent reviewers (T.L. and A.D.) using a predetermined data sheet. The same 2 reviewers were used for all steps of the review process, data were independently obtained, and any discrepancy was introduced for a third opinion (D.H.) and agreed upon by the majority.

Quality Assessment—The level of evidence was evaluated based on the criteria of the Oxford Centre for Evidence-Based Medicine. Two reviewers (T.L. and A.D.) graded each article included in the review.

Results

A total of 25 articles were reviewed. After the titles and abstracts were screened for relevance, 12 articles remained (Figure 1). Of these, 1 compared basal cell carcinoma (BCC) and squamous cell carcinoma (SCC), 4 were related to BCC, 3 were related to SCC, 1 was related to microcystic adnexal carcinoma (MAC), 1 was related to primary cutaneous adenoid cystic carcinoma (PCACC), and 2 were related to technical aspects of the staining process (Table 1).

A majority of the articles included in this review were qualitative and observational in nature, describing the staining characteristics of TB. Study characteristics are summarized in Table 1.

Comment

Basal Cell Carcinoma—Toluidine blue staining characteristics help to identify BCC nests by differentiating them from hair follicles in frozen sections. The metachromatic characteristic of TB stains the inner root sheath deep blue and highlights the surrounding stromal mucin of BCC a magenta color.^18,19 In hematoxylin and eosin (H&E) stains, these 2 distinct structures can be differentiated by cleft formation around tumor nests, mitotic figures, and the lack of a fibrous sheath present in BCC tumors.²⁰ The advantages and limitations of TB staining of BCC are presented in Table 2.

Humphreys et al⁶ suggested a noticeable difference between H&E and TB in the staining of cellular and stromal components. The nuclear detail of tumor cells was subjectively sharper and clearer with TB staining. The staining of stromal components may provide the most assistance in locating BCC islands. Mucopolysaccharide staining may be absent in H&E but stain a deep magenta with TB. Although the presence of mucopolysaccharides does not specifically indicate a tumor, it may prompt further attention and provide an indicator for sparse and infiltrative tumor cells.⁶ The metachromatic stromal change may indicate a narrow tumor-free margin where additional deeper sections often reveal tumor that may warrant additional resection margin in more aggressive malignancies. In particular, sclerosing/morpheaform BCCs have been shown to induce glycosaminoglycan synthesis and are highlighted more readily with TB than with H&E when compared to surrounding tissue.²¹ This differentiation in staining has remained a popular reason to routinely incorporate TB into the staining of infiltrative and morpheaform variants of BCC. Additionally, stromal mast cells are believed to be more abundant in the stroma of BCC and are more readily visualized in tissue specimens stained with TB, appearing as bright purple metachromatic granules. These granules are larger than normal and are increased in number.⁶

The margin behavior of BCC stained with TB was further characterized by Goldberg et al,⁸ who coined the term setting sun sign, which may be present in sequential sections of a disappearing nodule of a BCC tumor. Stroma, inflammatory infiltrate, and mast cells produce a magenta glow surrounding BCC tumors that is reminiscent of a setting sun (Figure 2). Invasive BCC is considered variable in this presentation, primarily because of zones of cell-free fluid and edema or the second area of inflammatory cells. This unique sign may benefit the inspecting Mohs surgeon by providing a clue to an underlying process that may have residual BCC tumors. The setting sun sign also may assist in identifying exact surgical margins.⁸

The nasal surface has a predilection for BCC.²² The skin of the nose has numerous look-alike structures to consider for complete tumor removal and avoidance of unnecessary removal. One challenge is distinguishing follicular basaloid proliferations (FBP) from BCC, a scenario that is more common on the nose.²² When TB staining was used, the sensitivity for detecting FBP reached 100% in 34 cases reviewed by Donaldson and Weber.¹⁰ None of the cases examined showed TB metachromasia surrounding FBP, thus indicating that TB can dependably identify this benign entity. Conversely, 5% (N=279) of BCCs confirmed on H&E did not exhibit surrounding TB metachromasia. This finding is concerning regarding the specificity of TB staining for BCC, but the authors of this study suggested the possibility that these exceptions were benign “simulants” (ie, trichoepithelioma) of BCC.¹⁰

The use of TB also has been shown to be statistically beneficial in Mohs training. In a single-center, single-fellow experiment, the sensitivity and specificity of using TB for BCC were extrapolated.⁹ Using TB as an adjunct in deep sections showed superior sensitivity to H&E alone in identifying BCC, increasing sensitivity from 96.3% to 99.7%. In a cohort of 352 BCC excisions and frozen sections, only 1 BCC was not completely excised. If H&E only had been performed, the fellow would have missed 13 residual BCC tumors.⁹

Bennett and Taher⁷ described a case in which hyaluronic acid (HA) from a filler injection was confused with the HA surrounding BCC tumor nests. They found that when TB is used as an adjunct, the HA filler is easier to differentiate from the HA surrounding the BCC tumor nests. In frozen sections stained with TB, the HA filler appeared as an amorphous, metachromatic, reddish-purple, whereas the HA surrounding the BCC tumor nests appeared as a well-defined red. These findings were less obvious in the same sections stained with H&E alone.⁷

Squamous Cell Carcinoma—In early investigations, the utility of TB in identifying SCC in frozen sections was thought to be limited. The description by Humphreys and colleagues⁶ of staining characteristics in SCC suggested that the nuclear detail that H&E provides is more easily recognized. The deep aqua nuclear staining produced with TB was considered more difficult to observe than the cytoplasmic eosinophilia of pyknotic and keratinizing cells in H&E.⁶

Toluidine blue may be beneficial in providing unique staining characteristics to further detail tumors that are difficult to interpret, such as spindle cell SCC and perineural invasion of aggressive SCC. In H&E, squamous cells of spindle cell SCC (scSCC) blend into the background of inflammatory cells and can be perceptibly difficult to locate. A small cohort of 3 Mohs surgeons who routinely use H&E were surveyed on their ability to detect a proven scSCC in H&E or TB by photograph.¹² All 3 were able to detect the scSCC in the TB photographs, but only 2 of 3 were able to detect it in H&E photographs. All 3 surgeons agreed that TB was preferable to H&E for this tumor type. These findings suggested that TB may be superior and preferred over H&E for visualizing tumor cells of scSCC.¹² The TB staining characteristics of perineural invasion of aggressive SCC have been referred to as the perineural corona sign because of the bright magenta stain that forms around affected nerves.¹³ Drosou et al¹³ suggested that TB may enhance the diagnostic accuracy for perineural SCC.

Rare Tumors—The adjunctive use of TB with H&E has been examined in rare tumors. Published reports have highlighted its use in MMS for treating MAC and PCACC. Toluidine blue exhibits staining advantages for these tumors. It may render isolated nests and perineural invasion of MAC more easily visible on frozen section.¹⁵

Although PCACC is rare, the recurrence rate is high.²³ Toluidine blue has been used with MMS to ensure complete removal and higher cure rates. The metachromatic nature of TB is advantageous in staining the HA present in these tumors. Those who have reported the use of TB for PCACC prefer it to H&E for frozen sections.¹⁴

Technical Aspects—The staining time for TB-treated slides is reduced compared to H&E staining; staining can be efficiently done in frozen sections in less than 2.5 minutes using the method shown in Table 3.¹⁷ In comparison, typical H&E staining takes 9 minutes, and older TB techniques take 7 minutes.⁶

Conclusion

Toluidine blue may play an important and helpful role in the successful diagnosis and treatment of particular cutaneous tumors by providing additional diagnostic information. Although surgeons performing MMS will continue using the staining protocols with which they are most comfortable, adjunctive use of TB over time may provide an additional benefit at low risk for disrupting practice efficiency or workflow. Many Mohs surgeons are accustomed to using this stain, even preferring to interpret only TB-stained slides for cutaneous malignancy. Most published studies on this topic have been observational in nature, and additional controlled trials may be warranted to determine the effects on outcomes in real-world practice.

The Diagnosis: Carcinoma en Cuirasse

Histopathology demonstrated a cellular infiltrate filling the dermis with sparing of the papillary and superficial reticular dermis (Figure 1A). The cells were arranged in strands and cords that infiltrated between sclerotic collagen bundles. Cytomorphologically, the cells ranged from epithelioid with large vesicular nuclei and prominent nucleoli to cuboidal with hyperchromatic nuclei with irregular contours and a high nuclear to cytoplasmic ratio (Figure 1B). Occasional mitotic figures were identified, and cells demonstrated diffuse nuclear positivity for GATA-3 (Figure 1C); 55% of the cells demonstrated estrogen receptor positivity, and immunohistochemistry of progesterone receptors was negative. These findings confirmed our patient’s diagnosis of breast carcinoma en cuirasse (CeC) as the primary manifestation of metastatic invasive ductal carcinoma. Our patient was treated with intravenous chemotherapy and tamoxifen.

Histopathologic findings of morphea include thickened hyalinized collagen bundles and loss of adventitial fat.¹ A diagnosis of chronic radiation dermatitis was inconsistent with our patient’s medical history and biopsy results, as pathology should reveal hyalinized collagen or stellate radiation fibroblasts.^2,3 Nests of squamous epithelial cells with abundant eosinophilic cytoplasm and large vesicular nuclei were not seen, excluding squamous cell carcinoma as a possible diagnosis.⁴ Although sclerosing sweat duct carcinoma is characterized by infiltrating cords in sclerotic dermis, the cells were not arranged in ductlike structures 1– to 2–cell layers thick, excluding this diagnosis.⁵

Carcinoma en cuirasse—named for skin involvement that appears similar to the metal breastplate of a cuirassier—is a rare form of cutaneous metastasis that typically presents with extensive infiltrative plaques resulting in fibrosis of the skin and subcutaneous tissue.^6,7 Carcinoma en cuirasse most commonly metastasizes from the breast but also may represent metastases from the lungs, gastrointestinal tract, or genitourinary systems.⁸ In the setting of a primary breast malignancy, metastatic plaques of CeC tend to represent tumor recurrence following a mastectomy procedure; however, in rare cases CeC can present as the primary manifestation of breast cancer or as a result of untreated malignancy.^6,9 In our patient, CeC was the primary manifestation of metastatic invasive ductal carcinoma with additional paraneoplastic ichthyosis (Figure 2).

Carcinoma en cuirasse comprises 3% to 6% of cutaneous metastases originating from the breast.^10,11 Breast cancer is the most common primary neoplasm displaying extracutaneous metastasis, comprising 70% of all cutaneous metastases in females.¹¹ Cutaneous metastasis often indicates late stage of disease, portending a poor prognosis. In our patient, the cutaneous nodules were present for approximately 3 years prior to the diagnosis of stage IV invasive ductal cell carcinoma with metastasis to the skin and lungs. Prior to admission, she had not been diagnosed with breast cancer, thus no treatments had been administered. It is uncommon for CeC to present as the initial finding and without prior treatment of the underlying malignancy. The median length of survival after diagnosis of cutaneous metastasis from breast cancer is 13.8 months, with a 10-year survival rate of 3.1%.¹²

In addition to cutaneous metastasis, breast cancer also may present with paraneoplastic dermatoses such as ichthyosis.¹³ Ichthyosis is characterized by extreme dryness, flaking, thickening, and mild pruritus.¹⁴ It most commonly is an inherited condition, but it may be acquired due to malignancy. Acquired ichthyosis may manifest in systemic diseases including systemic lupus erythematosus, sarcoidosis, and hypothyroidism.15 Although acquired ichthyosis is rare, it has been reported in cases of internal malignancy, most commonly lymphoproliferative malignancies and less frequently carcinoma of the breasts, cervix, and lungs. Patients who acquire ichthyosis in association with malignancy usually present with late-stage disease.¹⁵ Our patient acquired ichthyosis 3 months prior to admission and had never experienced it previously. Although the exact mechanism for acquiring ichthyosis remains unknown, it is uncertain if ichthyosis associated with malignancy is paraneoplastic or a result of chemotherapy.^14,16 In this case, the patient had not yet started chemotherapy at the time of the ichthyosis diagnosis, suggesting a paraneoplastic etiology.

Carcinoma en cuirasse and paraneoplastic ichthyosis individually are extremely rare manifestations of breast cancer. Thus, it is even rarer for these conditions to present concurrently. Treatment options for CeC include chemotherapy, radiotherapy, hormonal antagonists, and snake venom.¹¹ Systemic chemotherapy targeting the histopathologic type of the primary tumor is the treatment of choice. Other treatment methods usually are chosen for late stages of disease progression.10 Paraneoplastic ichthyosis has been reported to show improvement with treatment of the underlying primary malignancy by surgical removal or chemotherapy.^14,17 Tamoxifen less commonly is used for systemic treatment of CeC, but one case in the literature reported favorable outcomes.¹⁸

We describe 2 rare cutaneous manifestations of breast cancer occurring concomitantly: CeC and paraneoplastic ichthyosis. The combination of clinical and pathologic findings presented in this case solidified the diagnosis of metastatic invasive ductal carcinoma. We aim to improve recognition of paraneoplastic skin findings to accelerate the process of effective and efficient treatment.

The Diagnosis: Carcinoma en Cuirasse

Histopathology demonstrated a cellular infiltrate filling the dermis with sparing of the papillary and superficial reticular dermis (Figure 1A). The cells were arranged in strands and cords that infiltrated between sclerotic collagen bundles. Cytomorphologically, the cells ranged from epithelioid with large vesicular nuclei and prominent nucleoli to cuboidal with hyperchromatic nuclei with irregular contours and a high nuclear to cytoplasmic ratio (Figure 1B). Occasional mitotic figures were identified, and cells demonstrated diffuse nuclear positivity for GATA-3 (Figure 1C); 55% of the cells demonstrated estrogen receptor positivity, and immunohistochemistry of progesterone receptors was negative. These findings confirmed our patient’s diagnosis of breast carcinoma en cuirasse (CeC) as the primary manifestation of metastatic invasive ductal carcinoma. Our patient was treated with intravenous chemotherapy and tamoxifen.

Histopathologic findings of morphea include thickened hyalinized collagen bundles and loss of adventitial fat.¹ A diagnosis of chronic radiation dermatitis was inconsistent with our patient’s medical history and biopsy results, as pathology should reveal hyalinized collagen or stellate radiation fibroblasts.^2,3 Nests of squamous epithelial cells with abundant eosinophilic cytoplasm and large vesicular nuclei were not seen, excluding squamous cell carcinoma as a possible diagnosis.⁴ Although sclerosing sweat duct carcinoma is characterized by infiltrating cords in sclerotic dermis, the cells were not arranged in ductlike structures 1– to 2–cell layers thick, excluding this diagnosis.⁵

Carcinoma en cuirasse—named for skin involvement that appears similar to the metal breastplate of a cuirassier—is a rare form of cutaneous metastasis that typically presents with extensive infiltrative plaques resulting in fibrosis of the skin and subcutaneous tissue.^6,7 Carcinoma en cuirasse most commonly metastasizes from the breast but also may represent metastases from the lungs, gastrointestinal tract, or genitourinary systems.⁸ In the setting of a primary breast malignancy, metastatic plaques of CeC tend to represent tumor recurrence following a mastectomy procedure; however, in rare cases CeC can present as the primary manifestation of breast cancer or as a result of untreated malignancy.^6,9 In our patient, CeC was the primary manifestation of metastatic invasive ductal carcinoma with additional paraneoplastic ichthyosis (Figure 2).

Carcinoma en cuirasse comprises 3% to 6% of cutaneous metastases originating from the breast.^10,11 Breast cancer is the most common primary neoplasm displaying extracutaneous metastasis, comprising 70% of all cutaneous metastases in females.¹¹ Cutaneous metastasis often indicates late stage of disease, portending a poor prognosis. In our patient, the cutaneous nodules were present for approximately 3 years prior to the diagnosis of stage IV invasive ductal cell carcinoma with metastasis to the skin and lungs. Prior to admission, she had not been diagnosed with breast cancer, thus no treatments had been administered. It is uncommon for CeC to present as the initial finding and without prior treatment of the underlying malignancy. The median length of survival after diagnosis of cutaneous metastasis from breast cancer is 13.8 months, with a 10-year survival rate of 3.1%.¹²

In addition to cutaneous metastasis, breast cancer also may present with paraneoplastic dermatoses such as ichthyosis.¹³ Ichthyosis is characterized by extreme dryness, flaking, thickening, and mild pruritus.¹⁴ It most commonly is an inherited condition, but it may be acquired due to malignancy. Acquired ichthyosis may manifest in systemic diseases including systemic lupus erythematosus, sarcoidosis, and hypothyroidism.15 Although acquired ichthyosis is rare, it has been reported in cases of internal malignancy, most commonly lymphoproliferative malignancies and less frequently carcinoma of the breasts, cervix, and lungs. Patients who acquire ichthyosis in association with malignancy usually present with late-stage disease.¹⁵ Our patient acquired ichthyosis 3 months prior to admission and had never experienced it previously. Although the exact mechanism for acquiring ichthyosis remains unknown, it is uncertain if ichthyosis associated with malignancy is paraneoplastic or a result of chemotherapy.^14,16 In this case, the patient had not yet started chemotherapy at the time of the ichthyosis diagnosis, suggesting a paraneoplastic etiology.

Carcinoma en cuirasse and paraneoplastic ichthyosis individually are extremely rare manifestations of breast cancer. Thus, it is even rarer for these conditions to present concurrently. Treatment options for CeC include chemotherapy, radiotherapy, hormonal antagonists, and snake venom.¹¹ Systemic chemotherapy targeting the histopathologic type of the primary tumor is the treatment of choice. Other treatment methods usually are chosen for late stages of disease progression.10 Paraneoplastic ichthyosis has been reported to show improvement with treatment of the underlying primary malignancy by surgical removal or chemotherapy.^14,17 Tamoxifen less commonly is used for systemic treatment of CeC, but one case in the literature reported favorable outcomes.¹⁸

We describe 2 rare cutaneous manifestations of breast cancer occurring concomitantly: CeC and paraneoplastic ichthyosis. The combination of clinical and pathologic findings presented in this case solidified the diagnosis of metastatic invasive ductal carcinoma. We aim to improve recognition of paraneoplastic skin findings to accelerate the process of effective and efficient treatment.

The Diagnosis: Carcinoma en Cuirasse

Histopathology demonstrated a cellular infiltrate filling the dermis with sparing of the papillary and superficial reticular dermis (Figure 1A). The cells were arranged in strands and cords that infiltrated between sclerotic collagen bundles. Cytomorphologically, the cells ranged from epithelioid with large vesicular nuclei and prominent nucleoli to cuboidal with hyperchromatic nuclei with irregular contours and a high nuclear to cytoplasmic ratio (Figure 1B). Occasional mitotic figures were identified, and cells demonstrated diffuse nuclear positivity for GATA-3 (Figure 1C); 55% of the cells demonstrated estrogen receptor positivity, and immunohistochemistry of progesterone receptors was negative. These findings confirmed our patient’s diagnosis of breast carcinoma en cuirasse (CeC) as the primary manifestation of metastatic invasive ductal carcinoma. Our patient was treated with intravenous chemotherapy and tamoxifen.

Histopathologic findings of morphea include thickened hyalinized collagen bundles and loss of adventitial fat.¹ A diagnosis of chronic radiation dermatitis was inconsistent with our patient’s medical history and biopsy results, as pathology should reveal hyalinized collagen or stellate radiation fibroblasts.^2,3 Nests of squamous epithelial cells with abundant eosinophilic cytoplasm and large vesicular nuclei were not seen, excluding squamous cell carcinoma as a possible diagnosis.⁴ Although sclerosing sweat duct carcinoma is characterized by infiltrating cords in sclerotic dermis, the cells were not arranged in ductlike structures 1– to 2–cell layers thick, excluding this diagnosis.⁵

Carcinoma en cuirasse—named for skin involvement that appears similar to the metal breastplate of a cuirassier—is a rare form of cutaneous metastasis that typically presents with extensive infiltrative plaques resulting in fibrosis of the skin and subcutaneous tissue.^6,7 Carcinoma en cuirasse most commonly metastasizes from the breast but also may represent metastases from the lungs, gastrointestinal tract, or genitourinary systems.⁸ In the setting of a primary breast malignancy, metastatic plaques of CeC tend to represent tumor recurrence following a mastectomy procedure; however, in rare cases CeC can present as the primary manifestation of breast cancer or as a result of untreated malignancy.^6,9 In our patient, CeC was the primary manifestation of metastatic invasive ductal carcinoma with additional paraneoplastic ichthyosis (Figure 2).

Carcinoma en cuirasse comprises 3% to 6% of cutaneous metastases originating from the breast.^10,11 Breast cancer is the most common primary neoplasm displaying extracutaneous metastasis, comprising 70% of all cutaneous metastases in females.¹¹ Cutaneous metastasis often indicates late stage of disease, portending a poor prognosis. In our patient, the cutaneous nodules were present for approximately 3 years prior to the diagnosis of stage IV invasive ductal cell carcinoma with metastasis to the skin and lungs. Prior to admission, she had not been diagnosed with breast cancer, thus no treatments had been administered. It is uncommon for CeC to present as the initial finding and without prior treatment of the underlying malignancy. The median length of survival after diagnosis of cutaneous metastasis from breast cancer is 13.8 months, with a 10-year survival rate of 3.1%.¹²

In addition to cutaneous metastasis, breast cancer also may present with paraneoplastic dermatoses such as ichthyosis.¹³ Ichthyosis is characterized by extreme dryness, flaking, thickening, and mild pruritus.¹⁴ It most commonly is an inherited condition, but it may be acquired due to malignancy. Acquired ichthyosis may manifest in systemic diseases including systemic lupus erythematosus, sarcoidosis, and hypothyroidism.15 Although acquired ichthyosis is rare, it has been reported in cases of internal malignancy, most commonly lymphoproliferative malignancies and less frequently carcinoma of the breasts, cervix, and lungs. Patients who acquire ichthyosis in association with malignancy usually present with late-stage disease.¹⁵ Our patient acquired ichthyosis 3 months prior to admission and had never experienced it previously. Although the exact mechanism for acquiring ichthyosis remains unknown, it is uncertain if ichthyosis associated with malignancy is paraneoplastic or a result of chemotherapy.^14,16 In this case, the patient had not yet started chemotherapy at the time of the ichthyosis diagnosis, suggesting a paraneoplastic etiology.

Carcinoma en cuirasse and paraneoplastic ichthyosis individually are extremely rare manifestations of breast cancer. Thus, it is even rarer for these conditions to present concurrently. Treatment options for CeC include chemotherapy, radiotherapy, hormonal antagonists, and snake venom.¹¹ Systemic chemotherapy targeting the histopathologic type of the primary tumor is the treatment of choice. Other treatment methods usually are chosen for late stages of disease progression.10 Paraneoplastic ichthyosis has been reported to show improvement with treatment of the underlying primary malignancy by surgical removal or chemotherapy.^14,17 Tamoxifen less commonly is used for systemic treatment of CeC, but one case in the literature reported favorable outcomes.¹⁸

We describe 2 rare cutaneous manifestations of breast cancer occurring concomitantly: CeC and paraneoplastic ichthyosis. The combination of clinical and pathologic findings presented in this case solidified the diagnosis of metastatic invasive ductal carcinoma. We aim to improve recognition of paraneoplastic skin findings to accelerate the process of effective and efficient treatment.

The Diagnosis: Merkel Cell Carcinoma

Multiple diagnoses should be considered for a small, round, blue cell neoplasm of the skin, including both primary and metastatic entities. In our patient, histopathology revealed sheets and nests of infiltrative neoplastic cells with dispersed chromatin, minimal cytoplasm, and multiple mitoses (quiz image 1).¹ The lesional cells were in the dermis and superficial subcutaneous tissue but did not appear to be arising from the epidermis. Lymphovascular invasion also was evident on additional sections. Metastatic disease was identified in 3 sentinel lymph nodes from the right inguinal and right iliac regions. These features were compatible with a diagnosis of Merkel cell carcinoma (MCC).

Merkel cell carcinoma is a rare malignant neuroendocrine cutaneous tumor with a worldwide incidence of 0.1 to 1.6 cases per 100,000 individuals annually.² The typical patient is older than 75 years with fair skin and a history of extensive sun exposure. Immunocompromised individuals are predisposed and more susceptible to infection with the Merkel cell polyomavirus, which promotes oncogenesis in the majority of MCCs. Our patient’s history of combined variable immunodeficiency likely explains her presentation at a younger age.

The prognosis in patients with MCC is poor, with 5-year survival rates of 51% for local disease, 35% for nodal disease, and 14% for systemic metastases. Survival also is reduced in cases with head/ neck primary tumors and polyomavirus-negative tumors, as well as in immunocompromised patients.² Treatment of resectable MCC consists of Mohs micrographic surgery or wide local excision depending on the patient’s cosmetic concerns. Radiation therapy is recommended for cases with increased risk for recurrence or positive surgical margins, as well as when additional resection is impossible. A study investigating immunotherapy with nivolumab demonstrated complete pathologic response and radiographic tumor regression in nearly half of patients when given 4 weeks prior to surgery.³

Immunohistochemistry is essential in discerning MCC from other small blue cell tumors. Most MCC cases show positive expression of neuroendocrine markers such as synaptophysin, chromogranin, and insulinomaassociated protein 1. Perinuclear dotlike staining with cytokeratin (CK) 20 (quiz image 2) commonly is seen, but up to 15% of cases may be CK20 negative. Many of these CK20-negative cases also express CK7. This tumor also may stain with paired box 5 (PAX-5), CD99, terminal deoxynucleotidyl transferase, Ber-EP4, and CD117^1,4; melanoma stains (ie, human melanoma black [HMB] 45, SRYrelated HMB-box 10 [SOX-10], S-100, melanoma antigen recognized by T-cells 1 [MART-1]) should be negative. However, PAX-5 expression may be a potential pitfall given that B-cell lymphomas also would express that marker and could mimic MCC histologically. Therefore, other universal lymphoid markers such as CD45 should be ordered to rule out this entity. Even with one or a few aberrant stains, a diagnosis of MCC still can be rendered using the histomorphology and the overall staining profile.⁴ Of prognostic significance, p63 expression is associated with more aggressive tumors, while Bcl-2 expression is favorable, as it offers an additional targeted treatment option.^5,6

Basal cell carcinoma (BCC) is linked to excessive sun exposure and is the most common skin cancer. Similar to MCC, it typically is mitotically active and hyperchromatic; however, lymphovascular invasion or metastasis almost never is observed in BCC, whereas approximately one-third of MCC cases have metastasized by the time of diagnosis. Additionally, BCC lacks the perinuclear dotlike staining seen with CK20.^2,7 Features present in BCC that are unusual for MCC include peripheral nuclear palisading, mucin, and retraction artifact on paraffin-embedded sections (Figure 1).⁷

Leukemia cutis (or cutaneous infiltrates of leukemia) commonly displays a perivascular and periadnexal pattern in the dermis and subcutis. These infiltrates of neoplastic leukocytes can congregate into sheets, sometimes with an overlying Grenz zone, or form single-file infiltrates (Figure 2).^1,4 The neoplastic cells can be monomorphic or atypical and commonly are susceptible to crush artifact.⁴ Although the immunohistochemical profile varies depending on the etiology of the underlying leukemia, broad hematologic markers such as CD43 and CD45 are helpful to discern these malignancies from MCC.⁴

Being neuroendocrine in origin, metastatic small cell carcinoma (Figure 3) strongly mimics MCC histologically and usually stains with synaptophysin, chromogranin, and insulinoma-associated protein 1. Both tumor cells typically exhibit nuclear molding and high mitotic rates. Although small cell carcinoma is more likely to stain with high-molecular-weight cytokeratins (ie, CK7), it is not uncommon for these tumors to express lowmolecular- weight cytokeratins such as CK20. Because most cases originate from the lungs, these lesions should be positive for thyroid transcription factor 1 and negative for PAX-5, whereas MCC would show the reverse for those stains.¹ Ultimately, however, clinical correlation with imaging results is the single best methodology for differentiation.

Small cell melanoma, a variant of nevoid melanoma, can strongly resemble an MCC or a lymphoma. Usually located on the scalp or arising from a congenital nevus, small cell melanomas are aggressive and confer an unfavorable prognosis. Histologically, they consist of nests to sheets of atypical cells within the epidermis and dermis. These cells typically exhibit hyperchromatic nuclei, minimal cytoplasm, and frequent mitoses (Figure 4). Furthermore, the cells do not display maturation based on depth.⁸ These tumors usually are positive for HMB45, S-100, MART-1, SOX-10, and tyrosinase, all of which are extremely unlikely to stain an MCC.¹

The Diagnosis: Merkel Cell Carcinoma

Multiple diagnoses should be considered for a small, round, blue cell neoplasm of the skin, including both primary and metastatic entities. In our patient, histopathology revealed sheets and nests of infiltrative neoplastic cells with dispersed chromatin, minimal cytoplasm, and multiple mitoses (quiz image 1).¹ The lesional cells were in the dermis and superficial subcutaneous tissue but did not appear to be arising from the epidermis. Lymphovascular invasion also was evident on additional sections. Metastatic disease was identified in 3 sentinel lymph nodes from the right inguinal and right iliac regions. These features were compatible with a diagnosis of Merkel cell carcinoma (MCC).

Merkel cell carcinoma is a rare malignant neuroendocrine cutaneous tumor with a worldwide incidence of 0.1 to 1.6 cases per 100,000 individuals annually.² The typical patient is older than 75 years with fair skin and a history of extensive sun exposure. Immunocompromised individuals are predisposed and more susceptible to infection with the Merkel cell polyomavirus, which promotes oncogenesis in the majority of MCCs. Our patient’s history of combined variable immunodeficiency likely explains her presentation at a younger age.

The prognosis in patients with MCC is poor, with 5-year survival rates of 51% for local disease, 35% for nodal disease, and 14% for systemic metastases. Survival also is reduced in cases with head/ neck primary tumors and polyomavirus-negative tumors, as well as in immunocompromised patients.² Treatment of resectable MCC consists of Mohs micrographic surgery or wide local excision depending on the patient’s cosmetic concerns. Radiation therapy is recommended for cases with increased risk for recurrence or positive surgical margins, as well as when additional resection is impossible. A study investigating immunotherapy with nivolumab demonstrated complete pathologic response and radiographic tumor regression in nearly half of patients when given 4 weeks prior to surgery.³

Immunohistochemistry is essential in discerning MCC from other small blue cell tumors. Most MCC cases show positive expression of neuroendocrine markers such as synaptophysin, chromogranin, and insulinomaassociated protein 1. Perinuclear dotlike staining with cytokeratin (CK) 20 (quiz image 2) commonly is seen, but up to 15% of cases may be CK20 negative. Many of these CK20-negative cases also express CK7. This tumor also may stain with paired box 5 (PAX-5), CD99, terminal deoxynucleotidyl transferase, Ber-EP4, and CD117^1,4; melanoma stains (ie, human melanoma black [HMB] 45, SRYrelated HMB-box 10 [SOX-10], S-100, melanoma antigen recognized by T-cells 1 [MART-1]) should be negative. However, PAX-5 expression may be a potential pitfall given that B-cell lymphomas also would express that marker and could mimic MCC histologically. Therefore, other universal lymphoid markers such as CD45 should be ordered to rule out this entity. Even with one or a few aberrant stains, a diagnosis of MCC still can be rendered using the histomorphology and the overall staining profile.⁴ Of prognostic significance, p63 expression is associated with more aggressive tumors, while Bcl-2 expression is favorable, as it offers an additional targeted treatment option.^5,6

Basal cell carcinoma (BCC) is linked to excessive sun exposure and is the most common skin cancer. Similar to MCC, it typically is mitotically active and hyperchromatic; however, lymphovascular invasion or metastasis almost never is observed in BCC, whereas approximately one-third of MCC cases have metastasized by the time of diagnosis. Additionally, BCC lacks the perinuclear dotlike staining seen with CK20.^2,7 Features present in BCC that are unusual for MCC include peripheral nuclear palisading, mucin, and retraction artifact on paraffin-embedded sections (Figure 1).⁷

Leukemia cutis (or cutaneous infiltrates of leukemia) commonly displays a perivascular and periadnexal pattern in the dermis and subcutis. These infiltrates of neoplastic leukocytes can congregate into sheets, sometimes with an overlying Grenz zone, or form single-file infiltrates (Figure 2).^1,4 The neoplastic cells can be monomorphic or atypical and commonly are susceptible to crush artifact.⁴ Although the immunohistochemical profile varies depending on the etiology of the underlying leukemia, broad hematologic markers such as CD43 and CD45 are helpful to discern these malignancies from MCC.⁴

Being neuroendocrine in origin, metastatic small cell carcinoma (Figure 3) strongly mimics MCC histologically and usually stains with synaptophysin, chromogranin, and insulinoma-associated protein 1. Both tumor cells typically exhibit nuclear molding and high mitotic rates. Although small cell carcinoma is more likely to stain with high-molecular-weight cytokeratins (ie, CK7), it is not uncommon for these tumors to express lowmolecular- weight cytokeratins such as CK20. Because most cases originate from the lungs, these lesions should be positive for thyroid transcription factor 1 and negative for PAX-5, whereas MCC would show the reverse for those stains.¹ Ultimately, however, clinical correlation with imaging results is the single best methodology for differentiation.

Small cell melanoma, a variant of nevoid melanoma, can strongly resemble an MCC or a lymphoma. Usually located on the scalp or arising from a congenital nevus, small cell melanomas are aggressive and confer an unfavorable prognosis. Histologically, they consist of nests to sheets of atypical cells within the epidermis and dermis. These cells typically exhibit hyperchromatic nuclei, minimal cytoplasm, and frequent mitoses (Figure 4). Furthermore, the cells do not display maturation based on depth.⁸ These tumors usually are positive for HMB45, S-100, MART-1, SOX-10, and tyrosinase, all of which are extremely unlikely to stain an MCC.¹

The Diagnosis: Merkel Cell Carcinoma

Multiple diagnoses should be considered for a small, round, blue cell neoplasm of the skin, including both primary and metastatic entities. In our patient, histopathology revealed sheets and nests of infiltrative neoplastic cells with dispersed chromatin, minimal cytoplasm, and multiple mitoses (quiz image 1).¹ The lesional cells were in the dermis and superficial subcutaneous tissue but did not appear to be arising from the epidermis. Lymphovascular invasion also was evident on additional sections. Metastatic disease was identified in 3 sentinel lymph nodes from the right inguinal and right iliac regions. These features were compatible with a diagnosis of Merkel cell carcinoma (MCC).

Merkel cell carcinoma is a rare malignant neuroendocrine cutaneous tumor with a worldwide incidence of 0.1 to 1.6 cases per 100,000 individuals annually.² The typical patient is older than 75 years with fair skin and a history of extensive sun exposure. Immunocompromised individuals are predisposed and more susceptible to infection with the Merkel cell polyomavirus, which promotes oncogenesis in the majority of MCCs. Our patient’s history of combined variable immunodeficiency likely explains her presentation at a younger age.

The prognosis in patients with MCC is poor, with 5-year survival rates of 51% for local disease, 35% for nodal disease, and 14% for systemic metastases. Survival also is reduced in cases with head/ neck primary tumors and polyomavirus-negative tumors, as well as in immunocompromised patients.² Treatment of resectable MCC consists of Mohs micrographic surgery or wide local excision depending on the patient’s cosmetic concerns. Radiation therapy is recommended for cases with increased risk for recurrence or positive surgical margins, as well as when additional resection is impossible. A study investigating immunotherapy with nivolumab demonstrated complete pathologic response and radiographic tumor regression in nearly half of patients when given 4 weeks prior to surgery.³

Immunohistochemistry is essential in discerning MCC from other small blue cell tumors. Most MCC cases show positive expression of neuroendocrine markers such as synaptophysin, chromogranin, and insulinomaassociated protein 1. Perinuclear dotlike staining with cytokeratin (CK) 20 (quiz image 2) commonly is seen, but up to 15% of cases may be CK20 negative. Many of these CK20-negative cases also express CK7. This tumor also may stain with paired box 5 (PAX-5), CD99, terminal deoxynucleotidyl transferase, Ber-EP4, and CD117^1,4; melanoma stains (ie, human melanoma black [HMB] 45, SRYrelated HMB-box 10 [SOX-10], S-100, melanoma antigen recognized by T-cells 1 [MART-1]) should be negative. However, PAX-5 expression may be a potential pitfall given that B-cell lymphomas also would express that marker and could mimic MCC histologically. Therefore, other universal lymphoid markers such as CD45 should be ordered to rule out this entity. Even with one or a few aberrant stains, a diagnosis of MCC still can be rendered using the histomorphology and the overall staining profile.⁴ Of prognostic significance, p63 expression is associated with more aggressive tumors, while Bcl-2 expression is favorable, as it offers an additional targeted treatment option.^5,6

Basal cell carcinoma (BCC) is linked to excessive sun exposure and is the most common skin cancer. Similar to MCC, it typically is mitotically active and hyperchromatic; however, lymphovascular invasion or metastasis almost never is observed in BCC, whereas approximately one-third of MCC cases have metastasized by the time of diagnosis. Additionally, BCC lacks the perinuclear dotlike staining seen with CK20.^2,7 Features present in BCC that are unusual for MCC include peripheral nuclear palisading, mucin, and retraction artifact on paraffin-embedded sections (Figure 1).⁷

Leukemia cutis (or cutaneous infiltrates of leukemia) commonly displays a perivascular and periadnexal pattern in the dermis and subcutis. These infiltrates of neoplastic leukocytes can congregate into sheets, sometimes with an overlying Grenz zone, or form single-file infiltrates (Figure 2).^1,4 The neoplastic cells can be monomorphic or atypical and commonly are susceptible to crush artifact.⁴ Although the immunohistochemical profile varies depending on the etiology of the underlying leukemia, broad hematologic markers such as CD43 and CD45 are helpful to discern these malignancies from MCC.⁴

Being neuroendocrine in origin, metastatic small cell carcinoma (Figure 3) strongly mimics MCC histologically and usually stains with synaptophysin, chromogranin, and insulinoma-associated protein 1. Both tumor cells typically exhibit nuclear molding and high mitotic rates. Although small cell carcinoma is more likely to stain with high-molecular-weight cytokeratins (ie, CK7), it is not uncommon for these tumors to express lowmolecular- weight cytokeratins such as CK20. Because most cases originate from the lungs, these lesions should be positive for thyroid transcription factor 1 and negative for PAX-5, whereas MCC would show the reverse for those stains.¹ Ultimately, however, clinical correlation with imaging results is the single best methodology for differentiation.

Small cell melanoma, a variant of nevoid melanoma, can strongly resemble an MCC or a lymphoma. Usually located on the scalp or arising from a congenital nevus, small cell melanomas are aggressive and confer an unfavorable prognosis. Histologically, they consist of nests to sheets of atypical cells within the epidermis and dermis. These cells typically exhibit hyperchromatic nuclei, minimal cytoplasm, and frequent mitoses (Figure 4). Furthermore, the cells do not display maturation based on depth.⁸ These tumors usually are positive for HMB45, S-100, MART-1, SOX-10, and tyrosinase, all of which are extremely unlikely to stain an MCC.¹

TOPLINE:

Lower-extremity (LE) lymphedema increases the risk for all types of skin cancer on the lower extremities.

METHODOLOGY:

• In the retrospective cohort study, researchers reviewed reports at Mayo Clinic for all patients who had LE lymphedema, limiting the review to those who had an ICD code for lymphedema.
• 4,437 patients with the ICD code from 2000 to 2020 were compared with 4,437 matched controls.
• The records of patients with skin cancer diagnoses were reviewed manually to determine whether the skin cancer, its management, or both were a cause of lymphedema; cancers that caused secondary lymphedema were excluded.
• This is the first large-scale study evaluating the association between LE lymphedema and LE skin cancer.

TAKEAWAY:

• 211 patients (4.6%) in the LE lymphedema group had any ICD code for LE skin cancer, compared with 89 (2%) in the control group.
• Among those with LE lymphedema, the risk for skin cancer was 1.98 times greater compared with those without lymphedema (95% confidence interval, 1.43-2.74; P < .001). Cases included all types of skin cancer.
• Nineteen of 24 patients with unilateral LE lymphedema had a history of immunosuppression.
• In the group of 24 patients with unilateral LE lymphedema, the lymphedematous LE was more likely to have one or more skin cancers than were the unaffected LE (87.5% vs. 33.3%; P < .05), and skin cancer was 2.65 times more likely to develop on the affected LE than in the unaffected LE (95% CI, 1.17-5.99; P = .02).

IN PRACTICE:

“Our findings suggest the need for a relatively high degree of suspicion of skin cancer at sites with lymphedema,” senior author, Afsaneh Alavi, MD, professor of dermatology at the Mayo Clinic, said in a Mayo Clinic press release reporting the results.

SOURCE:

The study was conducted by researchers at the Mayo Clinic and Meharry Medical College, Nashville. It was published in the November 2023 Mayo Clinic Proceedings.

LIMITATIONS:

This was a single-center retrospective study, and patients with LE lymphedema may be overdiagnosed with LE skin cancer because they have a greater number of examinations.

DISCLOSURES:

Dr. Alavi reports having been a consultant for AbbVie, Boehringer Ingelheim, InflaRx, Novartis, and UCB SA and an investigator for Processa Pharmaceuticals and Boehringer Ingelheim. The other authors had no disclosures.

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

TOPLINE:

Lower-extremity (LE) lymphedema increases the risk for all types of skin cancer on the lower extremities.

METHODOLOGY:

• In the retrospective cohort study, researchers reviewed reports at Mayo Clinic for all patients who had LE lymphedema, limiting the review to those who had an ICD code for lymphedema.
• 4,437 patients with the ICD code from 2000 to 2020 were compared with 4,437 matched controls.
• The records of patients with skin cancer diagnoses were reviewed manually to determine whether the skin cancer, its management, or both were a cause of lymphedema; cancers that caused secondary lymphedema were excluded.
• This is the first large-scale study evaluating the association between LE lymphedema and LE skin cancer.

TAKEAWAY:

• 211 patients (4.6%) in the LE lymphedema group had any ICD code for LE skin cancer, compared with 89 (2%) in the control group.
• Among those with LE lymphedema, the risk for skin cancer was 1.98 times greater compared with those without lymphedema (95% confidence interval, 1.43-2.74; P < .001). Cases included all types of skin cancer.
• Nineteen of 24 patients with unilateral LE lymphedema had a history of immunosuppression.
• In the group of 24 patients with unilateral LE lymphedema, the lymphedematous LE was more likely to have one or more skin cancers than were the unaffected LE (87.5% vs. 33.3%; P < .05), and skin cancer was 2.65 times more likely to develop on the affected LE than in the unaffected LE (95% CI, 1.17-5.99; P = .02).

IN PRACTICE:

“Our findings suggest the need for a relatively high degree of suspicion of skin cancer at sites with lymphedema,” senior author, Afsaneh Alavi, MD, professor of dermatology at the Mayo Clinic, said in a Mayo Clinic press release reporting the results.

SOURCE:

The study was conducted by researchers at the Mayo Clinic and Meharry Medical College, Nashville. It was published in the November 2023 Mayo Clinic Proceedings.

LIMITATIONS:

This was a single-center retrospective study, and patients with LE lymphedema may be overdiagnosed with LE skin cancer because they have a greater number of examinations.

DISCLOSURES:

Dr. Alavi reports having been a consultant for AbbVie, Boehringer Ingelheim, InflaRx, Novartis, and UCB SA and an investigator for Processa Pharmaceuticals and Boehringer Ingelheim. The other authors had no disclosures.

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

TOPLINE:

Lower-extremity (LE) lymphedema increases the risk for all types of skin cancer on the lower extremities.

METHODOLOGY:

• In the retrospective cohort study, researchers reviewed reports at Mayo Clinic for all patients who had LE lymphedema, limiting the review to those who had an ICD code for lymphedema.
• 4,437 patients with the ICD code from 2000 to 2020 were compared with 4,437 matched controls.
• The records of patients with skin cancer diagnoses were reviewed manually to determine whether the skin cancer, its management, or both were a cause of lymphedema; cancers that caused secondary lymphedema were excluded.
• This is the first large-scale study evaluating the association between LE lymphedema and LE skin cancer.

TAKEAWAY:

• 211 patients (4.6%) in the LE lymphedema group had any ICD code for LE skin cancer, compared with 89 (2%) in the control group.
• Among those with LE lymphedema, the risk for skin cancer was 1.98 times greater compared with those without lymphedema (95% confidence interval, 1.43-2.74; P < .001). Cases included all types of skin cancer.
• Nineteen of 24 patients with unilateral LE lymphedema had a history of immunosuppression.
• In the group of 24 patients with unilateral LE lymphedema, the lymphedematous LE was more likely to have one or more skin cancers than were the unaffected LE (87.5% vs. 33.3%; P < .05), and skin cancer was 2.65 times more likely to develop on the affected LE than in the unaffected LE (95% CI, 1.17-5.99; P = .02).

IN PRACTICE:

“Our findings suggest the need for a relatively high degree of suspicion of skin cancer at sites with lymphedema,” senior author, Afsaneh Alavi, MD, professor of dermatology at the Mayo Clinic, said in a Mayo Clinic press release reporting the results.

SOURCE:

The study was conducted by researchers at the Mayo Clinic and Meharry Medical College, Nashville. It was published in the November 2023 Mayo Clinic Proceedings.

LIMITATIONS:

This was a single-center retrospective study, and patients with LE lymphedema may be overdiagnosed with LE skin cancer because they have a greater number of examinations.

DISCLOSURES:

Dr. Alavi reports having been a consultant for AbbVie, Boehringer Ingelheim, InflaRx, Novartis, and UCB SA and an investigator for Processa Pharmaceuticals and Boehringer Ingelheim. The other authors had no disclosures.

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

TOPLINE:

More than half of Mohs surgeons report at least one sharps injury in the past year, mostly self-inflicted, survey finds.

METHODOLOGY:

• Data on the incidence of sharps injuries among dermatologic surgeons is limited.
• In a cross-sectional analysis of anonymous survey responses from members of the American College of , researchers aimed to determine the incidence and types of sharps injuries among Mohs surgeons.
• The researchers used descriptive statistics for continuous and nominal variables (percentage and frequencies) to report survey data and Fisher exact or chi-square analysis of categorical variables to obtain P values.

TAKEAWAY:

• Of the 60 survey respondents, more than half (56.7%) were from single-specialty group practices, 26.6% were from academic practices, and fewer than half (43.3%) had been in practice for 15 or more years.
• In the past year, 56.7% of respondents experienced at least one sharps injury. Of these, 14.7% involved exposure to a blood-borne pathogen, which translated into an annual exposure risk of 7.6% for any given Mohs surgeon.
• The top two types of sharps injuries were self-inflicted suture needlestick (76.5%) and other types of self-inflicted needlestick injuries (26.5%).
• Of respondents who sustained a sharps injury, 44.1% did not report them, while 95% of all survey respondents said they had access to postexposure prophylaxis/protocols at their workplace.
• The researchers determined that the average annual rate of sharps injury was 0.87.

IN PRACTICE:

• “In best practices to prevent sharps injuries, the authors recommend that a standardized sharps handling protocol be developed and disseminated for dermatologic surgeons and their staff,” the researchers wrote.

STUDY DETAILS:

• Faezeh Talebi-Liasi, MD, and Jesse M. Lewin, MD, department of dermatology, Icahn School of Medicine at Mount Sinai, New York, conducted the research. The study was published in Dermatologic Surgery.

LIMITATIONS:

• The study’s cross-sectional observational design and small sample size was skewed toward single-specialty and academic practices.

DISCLOSURES:

• The authors reported having no relevant financial disclosures.

A version of this article appeared on Medscape.com.

TOPLINE:

More than half of Mohs surgeons report at least one sharps injury in the past year, mostly self-inflicted, survey finds.

METHODOLOGY:

• Data on the incidence of sharps injuries among dermatologic surgeons is limited.
• In a cross-sectional analysis of anonymous survey responses from members of the American College of , researchers aimed to determine the incidence and types of sharps injuries among Mohs surgeons.
• The researchers used descriptive statistics for continuous and nominal variables (percentage and frequencies) to report survey data and Fisher exact or chi-square analysis of categorical variables to obtain P values.

TAKEAWAY:

• Of the 60 survey respondents, more than half (56.7%) were from single-specialty group practices, 26.6% were from academic practices, and fewer than half (43.3%) had been in practice for 15 or more years.
• In the past year, 56.7% of respondents experienced at least one sharps injury. Of these, 14.7% involved exposure to a blood-borne pathogen, which translated into an annual exposure risk of 7.6% for any given Mohs surgeon.
• The top two types of sharps injuries were self-inflicted suture needlestick (76.5%) and other types of self-inflicted needlestick injuries (26.5%).
• Of respondents who sustained a sharps injury, 44.1% did not report them, while 95% of all survey respondents said they had access to postexposure prophylaxis/protocols at their workplace.
• The researchers determined that the average annual rate of sharps injury was 0.87.

IN PRACTICE:

• “In best practices to prevent sharps injuries, the authors recommend that a standardized sharps handling protocol be developed and disseminated for dermatologic surgeons and their staff,” the researchers wrote.

STUDY DETAILS:

• Faezeh Talebi-Liasi, MD, and Jesse M. Lewin, MD, department of dermatology, Icahn School of Medicine at Mount Sinai, New York, conducted the research. The study was published in Dermatologic Surgery.

LIMITATIONS:

• The study’s cross-sectional observational design and small sample size was skewed toward single-specialty and academic practices.

DISCLOSURES:

• The authors reported having no relevant financial disclosures.

A version of this article appeared on Medscape.com.

TOPLINE:

More than half of Mohs surgeons report at least one sharps injury in the past year, mostly self-inflicted, survey finds.

METHODOLOGY:

• Data on the incidence of sharps injuries among dermatologic surgeons is limited.
• In a cross-sectional analysis of anonymous survey responses from members of the American College of , researchers aimed to determine the incidence and types of sharps injuries among Mohs surgeons.
• The researchers used descriptive statistics for continuous and nominal variables (percentage and frequencies) to report survey data and Fisher exact or chi-square analysis of categorical variables to obtain P values.

TAKEAWAY:

• Of the 60 survey respondents, more than half (56.7%) were from single-specialty group practices, 26.6% were from academic practices, and fewer than half (43.3%) had been in practice for 15 or more years.
• In the past year, 56.7% of respondents experienced at least one sharps injury. Of these, 14.7% involved exposure to a blood-borne pathogen, which translated into an annual exposure risk of 7.6% for any given Mohs surgeon.
• The top two types of sharps injuries were self-inflicted suture needlestick (76.5%) and other types of self-inflicted needlestick injuries (26.5%).
• Of respondents who sustained a sharps injury, 44.1% did not report them, while 95% of all survey respondents said they had access to postexposure prophylaxis/protocols at their workplace.
• The researchers determined that the average annual rate of sharps injury was 0.87.

IN PRACTICE:

• “In best practices to prevent sharps injuries, the authors recommend that a standardized sharps handling protocol be developed and disseminated for dermatologic surgeons and their staff,” the researchers wrote.

STUDY DETAILS:

• Faezeh Talebi-Liasi, MD, and Jesse M. Lewin, MD, department of dermatology, Icahn School of Medicine at Mount Sinai, New York, conducted the research. The study was published in Dermatologic Surgery.

LIMITATIONS:

• The study’s cross-sectional observational design and small sample size was skewed toward single-specialty and academic practices.

DISCLOSURES:

• The authors reported having no relevant financial disclosures.

A version of this article appeared on Medscape.com.

TOPLINE:

Older adults with actinic keratoses (AKs) have a higher risk for skin cancers, including squamous cell carcinoma (SCC), basal cell carcinoma (BCC), and melanoma.

METHODOLOGY:

• AKs have been associated with a small risk for cutaneous SCC, but associations with risk for other skin cancers have not been well studied.
• AKs may be a marker of overall skin cancer risk, but guidelines for AK management lack recommendations for follow-up cancer surveillance.
• The researchers reviewed data from a random sample of 5 million fee-for-service Medicare beneficiaries treated for AKs from 2009 through 2018 in the United States. Patients with seborrheic keratoses (SKs) were included as comparators, and patients with a history of skin cancer were excluded.
• The primary outcome was the first surgically treated skin cancer, including SCC, BCC, and melanoma.

TAKEAWAY:

• A total of 555,945 adults with AKs and 481,024 with SKs were included. The mean age was approximately 74.0 years. More than half were female. Most were non-Hispanic White.
• Among patients with AKs, the absolute risk for any skin cancer after the first AK was 6.3%, 18.4%, and 28.5% at 1, 3, and 5 years, respectively.
• Patients with AKs had a significantly increased relative risk for any skin cancer compared with those with SKs (adjusted hazard ratio [aHR], 2.17) and separately for keratinocyte carcinoma (aHR, 2.20), SCC (aHR, 2.63), BCC (aHR, 1.85), and melanoma (aHR, 1.67).
• Although AKs are not considered a biological precursor of melanoma or BCC, the results suggest that AKs may be clinical indicators of increased UV exposure that subsequently increases the risk for skin cancer.

IN PRACTICE:

“The present results highlight the importance of developing evidence-based guidelines for follow-up skin cancer surveillance in patients with AKs, optimally including measures of AK burden,” the researchers wrote.

SOURCE:

The lead author on the study was Cassandra Mohr, BS, with corresponding author Mackenzie R. Wehner, MD, MPhil, of The University of Texas MD Anderson Cancer Center, Houston. The study was published online in JAMA Dermatology .

LIMITATIONS:

The study population of Medicare beneficiaries aged 65 years or older may not be a nationally representative sample, and surveillance bias may contribute to the increased risk for skin cancer in patients with AKs. The use of both ICD and CPT codes may underestimate the number of skin cancers because of cases that were treated nonsurgically.

DISCLOSURES:

The study was supported by the National Cancer Institute of the National Institutes of Health, the Cancer Prevention and Research Institute of Texas, and The University of Texas Rising STARS program. The researchers had no financial conflicts to disclose.

A version of this article appeared on Medscape.com.

TOPLINE:

Older adults with actinic keratoses (AKs) have a higher risk for skin cancers, including squamous cell carcinoma (SCC), basal cell carcinoma (BCC), and melanoma.

METHODOLOGY:

• AKs have been associated with a small risk for cutaneous SCC, but associations with risk for other skin cancers have not been well studied.
• AKs may be a marker of overall skin cancer risk, but guidelines for AK management lack recommendations for follow-up cancer surveillance.
• The researchers reviewed data from a random sample of 5 million fee-for-service Medicare beneficiaries treated for AKs from 2009 through 2018 in the United States. Patients with seborrheic keratoses (SKs) were included as comparators, and patients with a history of skin cancer were excluded.
• The primary outcome was the first surgically treated skin cancer, including SCC, BCC, and melanoma.

TAKEAWAY:

• A total of 555,945 adults with AKs and 481,024 with SKs were included. The mean age was approximately 74.0 years. More than half were female. Most were non-Hispanic White.
• Among patients with AKs, the absolute risk for any skin cancer after the first AK was 6.3%, 18.4%, and 28.5% at 1, 3, and 5 years, respectively.
• Patients with AKs had a significantly increased relative risk for any skin cancer compared with those with SKs (adjusted hazard ratio [aHR], 2.17) and separately for keratinocyte carcinoma (aHR, 2.20), SCC (aHR, 2.63), BCC (aHR, 1.85), and melanoma (aHR, 1.67).
• Although AKs are not considered a biological precursor of melanoma or BCC, the results suggest that AKs may be clinical indicators of increased UV exposure that subsequently increases the risk for skin cancer.

IN PRACTICE:

“The present results highlight the importance of developing evidence-based guidelines for follow-up skin cancer surveillance in patients with AKs, optimally including measures of AK burden,” the researchers wrote.

SOURCE:

The lead author on the study was Cassandra Mohr, BS, with corresponding author Mackenzie R. Wehner, MD, MPhil, of The University of Texas MD Anderson Cancer Center, Houston. The study was published online in JAMA Dermatology .

LIMITATIONS:

The study population of Medicare beneficiaries aged 65 years or older may not be a nationally representative sample, and surveillance bias may contribute to the increased risk for skin cancer in patients with AKs. The use of both ICD and CPT codes may underestimate the number of skin cancers because of cases that were treated nonsurgically.

DISCLOSURES:

The study was supported by the National Cancer Institute of the National Institutes of Health, the Cancer Prevention and Research Institute of Texas, and The University of Texas Rising STARS program. The researchers had no financial conflicts to disclose.

A version of this article appeared on Medscape.com.

TOPLINE:

Older adults with actinic keratoses (AKs) have a higher risk for skin cancers, including squamous cell carcinoma (SCC), basal cell carcinoma (BCC), and melanoma.

METHODOLOGY:

• AKs have been associated with a small risk for cutaneous SCC, but associations with risk for other skin cancers have not been well studied.
• AKs may be a marker of overall skin cancer risk, but guidelines for AK management lack recommendations for follow-up cancer surveillance.
• The researchers reviewed data from a random sample of 5 million fee-for-service Medicare beneficiaries treated for AKs from 2009 through 2018 in the United States. Patients with seborrheic keratoses (SKs) were included as comparators, and patients with a history of skin cancer were excluded.
• The primary outcome was the first surgically treated skin cancer, including SCC, BCC, and melanoma.

TAKEAWAY:

• A total of 555,945 adults with AKs and 481,024 with SKs were included. The mean age was approximately 74.0 years. More than half were female. Most were non-Hispanic White.
• Among patients with AKs, the absolute risk for any skin cancer after the first AK was 6.3%, 18.4%, and 28.5% at 1, 3, and 5 years, respectively.
• Patients with AKs had a significantly increased relative risk for any skin cancer compared with those with SKs (adjusted hazard ratio [aHR], 2.17) and separately for keratinocyte carcinoma (aHR, 2.20), SCC (aHR, 2.63), BCC (aHR, 1.85), and melanoma (aHR, 1.67).
• Although AKs are not considered a biological precursor of melanoma or BCC, the results suggest that AKs may be clinical indicators of increased UV exposure that subsequently increases the risk for skin cancer.

IN PRACTICE:

“The present results highlight the importance of developing evidence-based guidelines for follow-up skin cancer surveillance in patients with AKs, optimally including measures of AK burden,” the researchers wrote.

SOURCE:

The lead author on the study was Cassandra Mohr, BS, with corresponding author Mackenzie R. Wehner, MD, MPhil, of The University of Texas MD Anderson Cancer Center, Houston. The study was published online in JAMA Dermatology .

LIMITATIONS:

The study population of Medicare beneficiaries aged 65 years or older may not be a nationally representative sample, and surveillance bias may contribute to the increased risk for skin cancer in patients with AKs. The use of both ICD and CPT codes may underestimate the number of skin cancers because of cases that were treated nonsurgically.

DISCLOSURES:

The study was supported by the National Cancer Institute of the National Institutes of Health, the Cancer Prevention and Research Institute of Texas, and The University of Texas Rising STARS program. The researchers had no financial conflicts to disclose.

A version of this article appeared on Medscape.com.