Nonmelanoma Skin Cancer

Using a new system for classifying established prognostic features of lymph nodes may lead to better staging of oral cavity squamous cell cancer (OSCC) than the TNM staging system, experts say.

The TNM staging system is used by most facilities for cancer reporting, as defined by the National Cancer Institute. This system combines the size and extent of the primary tumor (T), the number of neighboring lymph nodes with cancer and subcategories (N), and whether or not metastasis has occurred (M).

In a new study published in the journal Cancer, the researchers created a novel classification system to better account for extranodal extension (ENE). The study population included 1460 adults with OSCC (696 with no lymph node involvement and 764 with positive lymph nodes), who underwent surgical resections at four centers.

“Our findings build on the growing evidence base that historical factors do not improve staging performance and that their omission results in improved N‐classification [i.e., the nodal status or lymph node involvement in cancer staging] performance,” John R. de Almeida, MD, of the University of Toronto, and colleagues, wrote in their new paper.

For patients with OSCC, this system, known as the 8th edition of American Joint Committee on Cancer/International Union Against Cancer TNM N‐classification (TNM‐8‐N), has several limitations, the researchers explained. These limitations include redundancy in the rare N3a category (i.e., having single or multiple lymph nodes greater than 6 cm or 3-7 lymph nodes without ENE) and the impact of ENE as a new prognostic feature, they said.

“Recent studies have shown that major ENE is associated with a significantly worse outcome than minor ENE, suggesting that these two subgroups should be considered as separate entities,” the authors wrote.
 

Study Methods and Results

The researchers created N-classifications based on adjusted hazard ratios and statistical analysis (recursive partitioning) with a focus on lymph node (LN) size and number and the extent of ENE. They compared their classifications of OSCC cases to those of the TNM-8-N’s classifications of the same cases.

Using the new classification system, lymph node number and size and the extent of ENE were associated with overall survival. The adjusted hazard ratios for LN counts of 1 vs. zero and greater than 1 vs. 0 were 1.92 and 3.21, respectively. The adjusted hazard ratios (aHRs) for LN size of greater than 3 cm vs. 3 cm or less, and for major vs. minor ENE were 1.88 and 1.40, respectively.

The use of an aHR improved cancer staging compared to the TNM-8-N by eliminating the N2c and 6-cm threshold, stratifying the extent of ENE, and stratifying N2b by 3-cm threshold, the researchers wrote.

The researchers compared their new system to the TNM-8 and also two other classification systems and their own recursive partitioning analysis (another statistical model).

The aHR-based system ranked first out of five in terms of correctly staging cancer, while the TNM-8 was fifth in the discovery cohort and fifth in the validation cohorts.

Outcome predictions (percentage variance explained) were 19.81 with the aHR vs. 18.95 in theTNM-8 in the discovery cohort, and similarly were 11.72 vs. 10.13, respectively, in the validation cohort.

“Overall, 25 patients staged as IVa in TNM‐8 were upstaged to IVb in the aHR proposal, and one patient staged as IVb was downstaged to IVa. Otherwise, overall stage between TNM‐8 and aHR remained the same,” the authors wrote.

“Our proposed N-classification based on aHR challenges previous tenets such as the importance of the 6-cm threshold and the importance of contralateral nodes,” the researchers wrote in their discussion.

The results from the new classification system were limited by the relatively small sample sizes and may not generalize to nonsquamous oral cancers, the researchers noted.

Further validation is needed before this system may be routinely applied in practice, but the results support evidence in favor of eliminating historical factors from staging, they said.
 

Experts Tout Advantages of Proposed Classification System

Cancer staging must be as accurate as possible and reviewed frequently, Shawn Li, MD, an otolaryngologist at University Hospitals, Cleveland, said in an interview. “This study aims to optimize nodal staging in oral cavity cancer. The current staging system doesn’t reflect updated data, and may not be specific enough to oral cavity cancers.”

This study notes the importance of stratifying extranodal extension (ENE) by micro (less than 2 mm) and macro (greater than 2 mm),” he said. It also points out that metastatic disease greater than 6 cm without ENE is infrequent enough not to require its own subcategory, he said.

Finally, in the new classification, proposed in this paper, “N2c was removed, because, statistically, it doesn’t seem to be a worse prognosis in cancers of the oral cavity,” he said.

“The data [described in this new paper] suggests that certain traditional criteria used in nodal staging for oral cavity cancer, such as [involving] very large lymph nodes greater than 6 cm in size and contralateral nodal involvement, may be less important than criteria that have not as of yet been incorporated into head and neck staging,” Wesley Talcott, MD, said in an interview. “The current study provides evidence that in oral cavity cancer, the prognostic accuracy of staging may improve by dropping these older criteria and incorporating degree of extranodal extension.”

This evidence is apparent in the ranking of the new aHR classification as first of the five strategies compared in the study, said Dr. Talcott, who was not involved in the study.

Highlighting the importance of microscopic vs. macroscopic extension may lead to doctors improving their identification of patients at highest risk for recurrence and refining treatment strategies, suggested Dr. Talcott, MD, a radiation oncologist at Northwell Health, New York, NY. However, a larger dataset is needed to validate the diagnostic accuracy of the authors’ proposed staging system, he said.

The TNM‐8‐N was updated in 2017, Dr. Li noted. “Since this system is widely referenced, it will likely need to be updated again before the changes in this study are widely adopted,” he said.

The study was supported by the National Institutes of Health and the National Cancer Institute. The researchers, Dr. Li, and Dr. Talcott had no financial conflicts to disclose.

Using a new system for classifying established prognostic features of lymph nodes may lead to better staging of oral cavity squamous cell cancer (OSCC) than the TNM staging system, experts say.

The TNM staging system is used by most facilities for cancer reporting, as defined by the National Cancer Institute. This system combines the size and extent of the primary tumor (T), the number of neighboring lymph nodes with cancer and subcategories (N), and whether or not metastasis has occurred (M).

In a new study published in the journal Cancer, the researchers created a novel classification system to better account for extranodal extension (ENE). The study population included 1460 adults with OSCC (696 with no lymph node involvement and 764 with positive lymph nodes), who underwent surgical resections at four centers.

“Our findings build on the growing evidence base that historical factors do not improve staging performance and that their omission results in improved N‐classification [i.e., the nodal status or lymph node involvement in cancer staging] performance,” John R. de Almeida, MD, of the University of Toronto, and colleagues, wrote in their new paper.

For patients with OSCC, this system, known as the 8th edition of American Joint Committee on Cancer/International Union Against Cancer TNM N‐classification (TNM‐8‐N), has several limitations, the researchers explained. These limitations include redundancy in the rare N3a category (i.e., having single or multiple lymph nodes greater than 6 cm or 3-7 lymph nodes without ENE) and the impact of ENE as a new prognostic feature, they said.

“Recent studies have shown that major ENE is associated with a significantly worse outcome than minor ENE, suggesting that these two subgroups should be considered as separate entities,” the authors wrote.
 

Study Methods and Results

The researchers created N-classifications based on adjusted hazard ratios and statistical analysis (recursive partitioning) with a focus on lymph node (LN) size and number and the extent of ENE. They compared their classifications of OSCC cases to those of the TNM-8-N’s classifications of the same cases.

Using the new classification system, lymph node number and size and the extent of ENE were associated with overall survival. The adjusted hazard ratios for LN counts of 1 vs. zero and greater than 1 vs. 0 were 1.92 and 3.21, respectively. The adjusted hazard ratios (aHRs) for LN size of greater than 3 cm vs. 3 cm or less, and for major vs. minor ENE were 1.88 and 1.40, respectively.

The use of an aHR improved cancer staging compared to the TNM-8-N by eliminating the N2c and 6-cm threshold, stratifying the extent of ENE, and stratifying N2b by 3-cm threshold, the researchers wrote.

The researchers compared their new system to the TNM-8 and also two other classification systems and their own recursive partitioning analysis (another statistical model).

The aHR-based system ranked first out of five in terms of correctly staging cancer, while the TNM-8 was fifth in the discovery cohort and fifth in the validation cohorts.

Outcome predictions (percentage variance explained) were 19.81 with the aHR vs. 18.95 in theTNM-8 in the discovery cohort, and similarly were 11.72 vs. 10.13, respectively, in the validation cohort.

“Overall, 25 patients staged as IVa in TNM‐8 were upstaged to IVb in the aHR proposal, and one patient staged as IVb was downstaged to IVa. Otherwise, overall stage between TNM‐8 and aHR remained the same,” the authors wrote.

“Our proposed N-classification based on aHR challenges previous tenets such as the importance of the 6-cm threshold and the importance of contralateral nodes,” the researchers wrote in their discussion.

The results from the new classification system were limited by the relatively small sample sizes and may not generalize to nonsquamous oral cancers, the researchers noted.

Further validation is needed before this system may be routinely applied in practice, but the results support evidence in favor of eliminating historical factors from staging, they said.
 

Experts Tout Advantages of Proposed Classification System

Cancer staging must be as accurate as possible and reviewed frequently, Shawn Li, MD, an otolaryngologist at University Hospitals, Cleveland, said in an interview. “This study aims to optimize nodal staging in oral cavity cancer. The current staging system doesn’t reflect updated data, and may not be specific enough to oral cavity cancers.”

This study notes the importance of stratifying extranodal extension (ENE) by micro (less than 2 mm) and macro (greater than 2 mm),” he said. It also points out that metastatic disease greater than 6 cm without ENE is infrequent enough not to require its own subcategory, he said.

Finally, in the new classification, proposed in this paper, “N2c was removed, because, statistically, it doesn’t seem to be a worse prognosis in cancers of the oral cavity,” he said.

“The data [described in this new paper] suggests that certain traditional criteria used in nodal staging for oral cavity cancer, such as [involving] very large lymph nodes greater than 6 cm in size and contralateral nodal involvement, may be less important than criteria that have not as of yet been incorporated into head and neck staging,” Wesley Talcott, MD, said in an interview. “The current study provides evidence that in oral cavity cancer, the prognostic accuracy of staging may improve by dropping these older criteria and incorporating degree of extranodal extension.”

This evidence is apparent in the ranking of the new aHR classification as first of the five strategies compared in the study, said Dr. Talcott, who was not involved in the study.

Highlighting the importance of microscopic vs. macroscopic extension may lead to doctors improving their identification of patients at highest risk for recurrence and refining treatment strategies, suggested Dr. Talcott, MD, a radiation oncologist at Northwell Health, New York, NY. However, a larger dataset is needed to validate the diagnostic accuracy of the authors’ proposed staging system, he said.

The TNM‐8‐N was updated in 2017, Dr. Li noted. “Since this system is widely referenced, it will likely need to be updated again before the changes in this study are widely adopted,” he said.

The study was supported by the National Institutes of Health and the National Cancer Institute. The researchers, Dr. Li, and Dr. Talcott had no financial conflicts to disclose.

Using a new system for classifying established prognostic features of lymph nodes may lead to better staging of oral cavity squamous cell cancer (OSCC) than the TNM staging system, experts say.

The TNM staging system is used by most facilities for cancer reporting, as defined by the National Cancer Institute. This system combines the size and extent of the primary tumor (T), the number of neighboring lymph nodes with cancer and subcategories (N), and whether or not metastasis has occurred (M).

In a new study published in the journal Cancer, the researchers created a novel classification system to better account for extranodal extension (ENE). The study population included 1460 adults with OSCC (696 with no lymph node involvement and 764 with positive lymph nodes), who underwent surgical resections at four centers.

“Our findings build on the growing evidence base that historical factors do not improve staging performance and that their omission results in improved N‐classification [i.e., the nodal status or lymph node involvement in cancer staging] performance,” John R. de Almeida, MD, of the University of Toronto, and colleagues, wrote in their new paper.

For patients with OSCC, this system, known as the 8th edition of American Joint Committee on Cancer/International Union Against Cancer TNM N‐classification (TNM‐8‐N), has several limitations, the researchers explained. These limitations include redundancy in the rare N3a category (i.e., having single or multiple lymph nodes greater than 6 cm or 3-7 lymph nodes without ENE) and the impact of ENE as a new prognostic feature, they said.

“Recent studies have shown that major ENE is associated with a significantly worse outcome than minor ENE, suggesting that these two subgroups should be considered as separate entities,” the authors wrote.
 

Study Methods and Results

The researchers created N-classifications based on adjusted hazard ratios and statistical analysis (recursive partitioning) with a focus on lymph node (LN) size and number and the extent of ENE. They compared their classifications of OSCC cases to those of the TNM-8-N’s classifications of the same cases.

Using the new classification system, lymph node number and size and the extent of ENE were associated with overall survival. The adjusted hazard ratios for LN counts of 1 vs. zero and greater than 1 vs. 0 were 1.92 and 3.21, respectively. The adjusted hazard ratios (aHRs) for LN size of greater than 3 cm vs. 3 cm or less, and for major vs. minor ENE were 1.88 and 1.40, respectively.

The use of an aHR improved cancer staging compared to the TNM-8-N by eliminating the N2c and 6-cm threshold, stratifying the extent of ENE, and stratifying N2b by 3-cm threshold, the researchers wrote.

The researchers compared their new system to the TNM-8 and also two other classification systems and their own recursive partitioning analysis (another statistical model).

The aHR-based system ranked first out of five in terms of correctly staging cancer, while the TNM-8 was fifth in the discovery cohort and fifth in the validation cohorts.

Outcome predictions (percentage variance explained) were 19.81 with the aHR vs. 18.95 in theTNM-8 in the discovery cohort, and similarly were 11.72 vs. 10.13, respectively, in the validation cohort.

“Overall, 25 patients staged as IVa in TNM‐8 were upstaged to IVb in the aHR proposal, and one patient staged as IVb was downstaged to IVa. Otherwise, overall stage between TNM‐8 and aHR remained the same,” the authors wrote.

“Our proposed N-classification based on aHR challenges previous tenets such as the importance of the 6-cm threshold and the importance of contralateral nodes,” the researchers wrote in their discussion.

The results from the new classification system were limited by the relatively small sample sizes and may not generalize to nonsquamous oral cancers, the researchers noted.

Further validation is needed before this system may be routinely applied in practice, but the results support evidence in favor of eliminating historical factors from staging, they said.
 

Experts Tout Advantages of Proposed Classification System

Cancer staging must be as accurate as possible and reviewed frequently, Shawn Li, MD, an otolaryngologist at University Hospitals, Cleveland, said in an interview. “This study aims to optimize nodal staging in oral cavity cancer. The current staging system doesn’t reflect updated data, and may not be specific enough to oral cavity cancers.”

This study notes the importance of stratifying extranodal extension (ENE) by micro (less than 2 mm) and macro (greater than 2 mm),” he said. It also points out that metastatic disease greater than 6 cm without ENE is infrequent enough not to require its own subcategory, he said.

Finally, in the new classification, proposed in this paper, “N2c was removed, because, statistically, it doesn’t seem to be a worse prognosis in cancers of the oral cavity,” he said.

“The data [described in this new paper] suggests that certain traditional criteria used in nodal staging for oral cavity cancer, such as [involving] very large lymph nodes greater than 6 cm in size and contralateral nodal involvement, may be less important than criteria that have not as of yet been incorporated into head and neck staging,” Wesley Talcott, MD, said in an interview. “The current study provides evidence that in oral cavity cancer, the prognostic accuracy of staging may improve by dropping these older criteria and incorporating degree of extranodal extension.”

This evidence is apparent in the ranking of the new aHR classification as first of the five strategies compared in the study, said Dr. Talcott, who was not involved in the study.

Highlighting the importance of microscopic vs. macroscopic extension may lead to doctors improving their identification of patients at highest risk for recurrence and refining treatment strategies, suggested Dr. Talcott, MD, a radiation oncologist at Northwell Health, New York, NY. However, a larger dataset is needed to validate the diagnostic accuracy of the authors’ proposed staging system, he said.

The TNM‐8‐N was updated in 2017, Dr. Li noted. “Since this system is widely referenced, it will likely need to be updated again before the changes in this study are widely adopted,” he said.

The study was supported by the National Institutes of Health and the National Cancer Institute. The researchers, Dr. Li, and Dr. Talcott had no financial conflicts to disclose.

When clinicians in a large-scale study viewed a series of digital images that showed skin diseases across skin tones and were asked to make a diagnosis, the accuracy was 38% among dermatologists and 19% among primary care physicians (PCPs). But when decision support from a deep learning system (DLS) was introduced, diagnostic accuracy increased by 33% among dermatologists and 69% among PCPs, results from a multicenter study showed.

However, the researchers found that across all images, diseases in dark skin (Fitzpatrick skin types 5 and 6) were diagnosed less accurately than diseases in light skin (Fitzpatrick skin types 1-4).

“These results contribute to an emerging literature on diagnostic accuracy disparities across patient skin tones and present evidence that the diagnostic accuracy of medical professionals on images of dark skin is lower than on images of light skin,” researchers led by Matthew Groh, PhD, of Northwestern University’s Kellogg School of Management, wrote in their study, published online in Nature Medicine.

For the study, 389 board-certified dermatologists and 450 PCPs in 39 countries were presented with 364 images to view spanning 46 skin diseases and asked to submit up to four differential diagnoses. Nearly 80% of the images were of 8 diseases: atopic dermatitis, cutaneous T-cell lymphoma (CTCL), dermatomyositis, lichen planus, Lyme disease, pityriasis rosea, pityriasis rubra pilaris, and secondary syphilis.

Dermatologists and PCPs achieved a diagnostic accuracy of 38% and 19%, respectively, but both groups of clinicians were 4 percentage points less accurate for diagnosis of images of dark skin as compared with light skin. With assistance from DLS decision support, diagnostic accuracy increased by 33% among dermatologists and 69% among primary care physicians. Among dermatologists, DLS support generally increased diagnostic accuracy evenly across skin tones. However, among PCPs, DLS support increased their diagnostic accuracy more in light skin tones than in dark ones.

In the survey component of the study, when the participants were asked, “Do you feel you received sufficient training for diagnosing skin diseases in patients with skin of color (non-white patients)?” 67% of all PCPs and 33% of all dermatologists responded no. “Furthermore, we have found differences in how often BCDs [board-certified dermatologists] and PCPs refer patients with light and dark skin for biopsy,” the authors wrote. “Specifically, for CTCL (a life-threatening disease), we found that both BCDs and PCPs report that they would refer patients for biopsy significantly more often in light skin than dark skin. Moreover, for the common skin diseases atopic dermatitis and pityriasis rosea, we found that BCDs report they would refer patients for biopsy more often in dark skin than light skin, which creates an unnecessary overburden on patients with dark skin.”

In a press release about the study, Dr. Groh emphasized that he and other scientists who investigate human-computer interaction “have to find a way to incorporate underrepresented demographics in our research. That way we will be ready to accurately implement these models in the real world and build AI systems that serve as tools that are designed to avoid the kind of systematic errors we know humans and machines are prone to. Then you can update curricula, you can change norms in different fields and hopefully everyone gets better.”

When clinicians in a large-scale study viewed a series of digital images that showed skin diseases across skin tones and were asked to make a diagnosis, the accuracy was 38% among dermatologists and 19% among primary care physicians (PCPs). But when decision support from a deep learning system (DLS) was introduced, diagnostic accuracy increased by 33% among dermatologists and 69% among PCPs, results from a multicenter study showed.

However, the researchers found that across all images, diseases in dark skin (Fitzpatrick skin types 5 and 6) were diagnosed less accurately than diseases in light skin (Fitzpatrick skin types 1-4).

“These results contribute to an emerging literature on diagnostic accuracy disparities across patient skin tones and present evidence that the diagnostic accuracy of medical professionals on images of dark skin is lower than on images of light skin,” researchers led by Matthew Groh, PhD, of Northwestern University’s Kellogg School of Management, wrote in their study, published online in Nature Medicine.

For the study, 389 board-certified dermatologists and 450 PCPs in 39 countries were presented with 364 images to view spanning 46 skin diseases and asked to submit up to four differential diagnoses. Nearly 80% of the images were of 8 diseases: atopic dermatitis, cutaneous T-cell lymphoma (CTCL), dermatomyositis, lichen planus, Lyme disease, pityriasis rosea, pityriasis rubra pilaris, and secondary syphilis.

Dermatologists and PCPs achieved a diagnostic accuracy of 38% and 19%, respectively, but both groups of clinicians were 4 percentage points less accurate for diagnosis of images of dark skin as compared with light skin. With assistance from DLS decision support, diagnostic accuracy increased by 33% among dermatologists and 69% among primary care physicians. Among dermatologists, DLS support generally increased diagnostic accuracy evenly across skin tones. However, among PCPs, DLS support increased their diagnostic accuracy more in light skin tones than in dark ones.

In the survey component of the study, when the participants were asked, “Do you feel you received sufficient training for diagnosing skin diseases in patients with skin of color (non-white patients)?” 67% of all PCPs and 33% of all dermatologists responded no. “Furthermore, we have found differences in how often BCDs [board-certified dermatologists] and PCPs refer patients with light and dark skin for biopsy,” the authors wrote. “Specifically, for CTCL (a life-threatening disease), we found that both BCDs and PCPs report that they would refer patients for biopsy significantly more often in light skin than dark skin. Moreover, for the common skin diseases atopic dermatitis and pityriasis rosea, we found that BCDs report they would refer patients for biopsy more often in dark skin than light skin, which creates an unnecessary overburden on patients with dark skin.”

In a press release about the study, Dr. Groh emphasized that he and other scientists who investigate human-computer interaction “have to find a way to incorporate underrepresented demographics in our research. That way we will be ready to accurately implement these models in the real world and build AI systems that serve as tools that are designed to avoid the kind of systematic errors we know humans and machines are prone to. Then you can update curricula, you can change norms in different fields and hopefully everyone gets better.”

When clinicians in a large-scale study viewed a series of digital images that showed skin diseases across skin tones and were asked to make a diagnosis, the accuracy was 38% among dermatologists and 19% among primary care physicians (PCPs). But when decision support from a deep learning system (DLS) was introduced, diagnostic accuracy increased by 33% among dermatologists and 69% among PCPs, results from a multicenter study showed.

However, the researchers found that across all images, diseases in dark skin (Fitzpatrick skin types 5 and 6) were diagnosed less accurately than diseases in light skin (Fitzpatrick skin types 1-4).

“These results contribute to an emerging literature on diagnostic accuracy disparities across patient skin tones and present evidence that the diagnostic accuracy of medical professionals on images of dark skin is lower than on images of light skin,” researchers led by Matthew Groh, PhD, of Northwestern University’s Kellogg School of Management, wrote in their study, published online in Nature Medicine.

For the study, 389 board-certified dermatologists and 450 PCPs in 39 countries were presented with 364 images to view spanning 46 skin diseases and asked to submit up to four differential diagnoses. Nearly 80% of the images were of 8 diseases: atopic dermatitis, cutaneous T-cell lymphoma (CTCL), dermatomyositis, lichen planus, Lyme disease, pityriasis rosea, pityriasis rubra pilaris, and secondary syphilis.

Dermatologists and PCPs achieved a diagnostic accuracy of 38% and 19%, respectively, but both groups of clinicians were 4 percentage points less accurate for diagnosis of images of dark skin as compared with light skin. With assistance from DLS decision support, diagnostic accuracy increased by 33% among dermatologists and 69% among primary care physicians. Among dermatologists, DLS support generally increased diagnostic accuracy evenly across skin tones. However, among PCPs, DLS support increased their diagnostic accuracy more in light skin tones than in dark ones.

In the survey component of the study, when the participants were asked, “Do you feel you received sufficient training for diagnosing skin diseases in patients with skin of color (non-white patients)?” 67% of all PCPs and 33% of all dermatologists responded no. “Furthermore, we have found differences in how often BCDs [board-certified dermatologists] and PCPs refer patients with light and dark skin for biopsy,” the authors wrote. “Specifically, for CTCL (a life-threatening disease), we found that both BCDs and PCPs report that they would refer patients for biopsy significantly more often in light skin than dark skin. Moreover, for the common skin diseases atopic dermatitis and pityriasis rosea, we found that BCDs report they would refer patients for biopsy more often in dark skin than light skin, which creates an unnecessary overburden on patients with dark skin.”

In a press release about the study, Dr. Groh emphasized that he and other scientists who investigate human-computer interaction “have to find a way to incorporate underrepresented demographics in our research. That way we will be ready to accurately implement these models in the real world and build AI systems that serve as tools that are designed to avoid the kind of systematic errors we know humans and machines are prone to. Then you can update curricula, you can change norms in different fields and hopefully everyone gets better.”

The patient had an advanced cutaneous squamous cell carcinoma (cSCC) on the face that seemed to be affecting the facial nerve, ruling out aggressive surgery. When Mohs surgery failed to clear the tumor, radiation was ordered. But the best option — an immune checkpoint inhibitor — could not be administered because the patient was a lung transplant recipient.

Although approved for metastatic cSCC, immune checkpoint inhibitors are associated with a higher potential for rejection of an organ transplant.

“The feeling is that the risk of rejection is just too great if we were to try to give an immune checkpoint inhibitor,” said Sean Christensen, MD, PhD, director of dermatologic surgery at Yale Dermatology–Branford, in Connecticut, who was treating the patient. Dr. Christensen consulted with the transplant team, and together they decided to switch the patient to sirolimus, an immunosuppressant that has been shown to have less risk of promoting skin cancer in those who take the medication. Sirolimus, however, is not as well tolerated as the usual first-line immunosuppressant, tacrolimus.

Dr. Christensen

Dr. Bottomley

Reducing Risk Factors

Dr. Bottomley said that there’s also been renewed effort to identify how to reduce cSCC risk in transplant recipients through recently developed consensus guidelines and a proposed decision framework developed by Dr. Bottomley and colleagues. The evidence will help clinicians have “greater confidence in making early interventions,” he said.

Currently, solid organ transplant patients are told to reduce sun exposure, in part because the majority of cSCCs occur in sun-exposed areas, such as the head and neck, and ultraviolet radiation leads to mutations. “Sun protection is critical,” Dr. Christensen said. That’s especially true in younger transplant recipients, who may have decades of sun exposure, he said.

The immunosuppressive medications also increase cancer risk, for a variety of reasons. One of the more-commonly used immunosuppressants in the past, azathioprine, is itself carcinogenic. Other antirejection medications, such as tacrolimus and mycophenolate, may also induce mutagenic changes that give rise to malignancies, according to the paper by Dr. Bibee, assistant professor of dermatology at Johns Hopkins, Baltimore.

Both Dr. Bibee, in her paper, and Dr. Arron, in an interview, noted that voriconazole, an antifungal used to prevent Aspergillus infection after lung transplant, has been associated with an increase in cSCC in lung transplant recipients.

Dr. Arron

In addition, immunosuppression essentially “blocks the body’s immune system from recognizing that there are abnormal cancerous cells present,” Dr. Arron, a dermatologist in private practice in Burlingame, California, told this news organization.

Previously, while at the High-Risk Skin Cancer Program at University of California, San Francisco (UCSF), Dr. Arron and others studied whether human papillomavirus (HPV) might play a role in spurring the development of cSCC formation in the immunocompromised. HPV is highly prevalent on the skin, but the virus found on the skin tends to be composed of lower-risk strains.

“In our research, we did not find any biologic mechanism by which this virus might be driving these cancers,” said Dr. Arron, although she said that some researchers “feel very strongly that HPV must be in some way a driver.”

Dr. Bottomley believes that HPV’s role has not been completely determined. The excess incidence of cSCC suggests a virus might be involved, as has been seen with excess risk of lymphoma in patients with Epstein-Barr virus, he said.

Some of his research is focusing on whether advanced immune aging is an independent risk factor for subsequent cSCC development in solid organ transplant recipients. The immune system undergoes changes as people age, and the speed of this process varies from patient to patient, which means immune age can be different from chronological age, said Dr. Bottomley. “We’re still exploring why immune aging should predispose you to cSCC,” he said.
 

When to Intervene?

Transplant patients are followed by dermatologists at regular intervals. But guidelines are not consistent on the recommended timing of those intervals.

Dr. Arron and colleagues in 2019 created a risk prediction module that recommended frequency of follow-up based on low, medium, high, or very high risk. The tool is available to clinicians in an app called SUNTRAC, or the Skin and Ultraviolet Neoplasia Transplant Risk Assessment Calculator.

A question that Dr. Arron said dermatologists and transplant specialists have wrangled with: How early can they intervene to prevent further lesions?

In the 2022 decision framework paper in Transplant International, Dr. Bottomley and dermatology colleagues from around the world attempted to better delineate when and how clinicians should intervene when a cSCC is first detected. That first cSCC “should be regarded as a ‘red flag’ heralding an increased risk of further skin cancers and possibly internal malignancies,” the authors wrote. That moment is “a key opportunity to proactively consider secondary preventive strategies,” they wrote, but noted that the best interventions and “their sequencing remain unclear,” indicating the need for further research.
 

Coordinating With the Transplant Team

A key strategy to help prevent cSCC development — suggested in Dr. Bottomley’s paper, and by Dr. Arron and Dr. Christensen — is to consult with the transplant team on potentially changing a patient’s immunosuppressive medication or reducing the dose.

Dr. Arron said that a decade ago, it was somewhat of a novel concept, requiring data-sharing and making personal connections with the transplant team to forge trusting relationships. By the time she left UCSF a few years ago, she said, “the transplant program was very much on board with preventing and treating skin cancer and oftentimes they were making changes even before I would suggest them.”

Suggesting a change or dose reduction is not undertaken lightly. “Our transplant physician colleagues are balancing multiple problems in very sick patients, of which skin cancer might be one, but not the most pressing one in the setting of other transplant complications,” said Dr. Arron.

Dr. Bottomley said that “as transplant physicians, we very much respect and value the input of our dermatology colleagues,” but agreed that many factors “outside malignancy risk” must be weighed when considering changing an immunosuppressive regimen.

In a Delphi Consensus Statement on prevention of cSCC in organ transplant recipients, published in 2021 in JAMA Dermatology, the authors recommended having discussions about immunosuppression with transplant specialists, but did not make a recommendation on what strategy to use. The consensus panel said it preferred “to defer this decision to transplant physicians.”

Acitretin a Go, Nicotinamide Not So Much

Outside of changing an immunosuppressive regimen, among the interventions for secondary prevention are acitretin, the systemic retinoid, and nicotinamide, a form of niacin.

Dr. Christensen conducted a small retrospective investigation evaluating the effectiveness of acitretin in reducing cSCC in both immunocompromised and immunocompetent patients who had received care at Yale, which was recently published in the Journal of the American Academy of Dermatology. Acitretin reduced invasive cSCC by about 75% in both patient groups — a surprising result for the immunocompetent group, but well-established in patients who have had a solid organ transplant. But acitretin had no effect on cSCC in situ or basal cell carcinoma. “The benefit of acitretin is primarily in preventing the invasive SCC,” said Dr. Christensen, which is why he tends to reserve it for patients who have already had several cSCCs.

“It’s not a completely benign medication,” he said, noting the need for monitoring for cholesterol and liver function.

Several years ago, a study in immunocompetent patients, published in the New England Journal of Medicine, found that nicotinamide (also known as niacinamide) reduced the rate of nonmelonoma skin cancer by 23%, giving clinicians hope that it might also be a low-risk, low-cost cancer preventive for solid organ transplant patients. But enthusiasm has dampened since a 2023 study in the New England Journal of Medicine found that the vitamin did not reduce cSCCs in transplant recipients.

Dr. Christensen said he believes the most-recent study wasn’t powered to detect a 25% reduction in cancers. “It’s certainly possible that it still works exactly the same way in transplant patients that it does in immunocompetent patients,” he said. “There’s very little risk of recommending it to patients for general prevention. But it probably has a very modest effect in many,” he said.

Dr. Arron agreed, saying, “it may be that we simply need bigger studies to achieve that statistical significance.” Even so, she said she would not use the therapy “until there is more evidence supporting the use of nicotinamide in transplant recipients.”

Immune checkpoint inhibitors such as cemiplimab and pembrolizumab have been approved by the US Food and Drug Administration for advanced cSCC; nivolumab is another drug in the same class that has not yet been approved for cSCC. But “there’s always been a fear — and a legitimate fear — that if you gave those to organ transplant recipients they would reject their organ,” said Dr. Christensen.

Patients who take the checkpoint inhibitors may first have to stop taking their antirejection drugs, leaving them at risk. It also appears that the checkpoint inhibitors themselves contribute to organ rejection. Recent studies suggest that “the rate of organ rejection is only about 30% to 40%,” with the checkpoint inhibitors, said Dr. Christensen. “Obviously that’s still not an ideal outcome,” he said, but noted that with patients who have inoperable metastatic cSCC, “immune therapy can be a good option.”

Dr. Christensen reported no disclosures. Dr. Bottomley has previously received speaker fees and an educational grant from Astellas. Dr. Arron disclosed ties with Regeneron, Castle Biosciences, and Enspectra Health, not specific to transplantation.

The patient had an advanced cutaneous squamous cell carcinoma (cSCC) on the face that seemed to be affecting the facial nerve, ruling out aggressive surgery. When Mohs surgery failed to clear the tumor, radiation was ordered. But the best option — an immune checkpoint inhibitor — could not be administered because the patient was a lung transplant recipient.

Although approved for metastatic cSCC, immune checkpoint inhibitors are associated with a higher potential for rejection of an organ transplant.

“The feeling is that the risk of rejection is just too great if we were to try to give an immune checkpoint inhibitor,” said Sean Christensen, MD, PhD, director of dermatologic surgery at Yale Dermatology–Branford, in Connecticut, who was treating the patient. Dr. Christensen consulted with the transplant team, and together they decided to switch the patient to sirolimus, an immunosuppressant that has been shown to have less risk of promoting skin cancer in those who take the medication. Sirolimus, however, is not as well tolerated as the usual first-line immunosuppressant, tacrolimus.

Dr. Christensen

Dr. Bottomley

Reducing Risk Factors

Dr. Bottomley said that there’s also been renewed effort to identify how to reduce cSCC risk in transplant recipients through recently developed consensus guidelines and a proposed decision framework developed by Dr. Bottomley and colleagues. The evidence will help clinicians have “greater confidence in making early interventions,” he said.

Currently, solid organ transplant patients are told to reduce sun exposure, in part because the majority of cSCCs occur in sun-exposed areas, such as the head and neck, and ultraviolet radiation leads to mutations. “Sun protection is critical,” Dr. Christensen said. That’s especially true in younger transplant recipients, who may have decades of sun exposure, he said.

The immunosuppressive medications also increase cancer risk, for a variety of reasons. One of the more-commonly used immunosuppressants in the past, azathioprine, is itself carcinogenic. Other antirejection medications, such as tacrolimus and mycophenolate, may also induce mutagenic changes that give rise to malignancies, according to the paper by Dr. Bibee, assistant professor of dermatology at Johns Hopkins, Baltimore.

Both Dr. Bibee, in her paper, and Dr. Arron, in an interview, noted that voriconazole, an antifungal used to prevent Aspergillus infection after lung transplant, has been associated with an increase in cSCC in lung transplant recipients.

Dr. Arron

In addition, immunosuppression essentially “blocks the body’s immune system from recognizing that there are abnormal cancerous cells present,” Dr. Arron, a dermatologist in private practice in Burlingame, California, told this news organization.

Previously, while at the High-Risk Skin Cancer Program at University of California, San Francisco (UCSF), Dr. Arron and others studied whether human papillomavirus (HPV) might play a role in spurring the development of cSCC formation in the immunocompromised. HPV is highly prevalent on the skin, but the virus found on the skin tends to be composed of lower-risk strains.

“In our research, we did not find any biologic mechanism by which this virus might be driving these cancers,” said Dr. Arron, although she said that some researchers “feel very strongly that HPV must be in some way a driver.”

Dr. Bottomley believes that HPV’s role has not been completely determined. The excess incidence of cSCC suggests a virus might be involved, as has been seen with excess risk of lymphoma in patients with Epstein-Barr virus, he said.

Some of his research is focusing on whether advanced immune aging is an independent risk factor for subsequent cSCC development in solid organ transplant recipients. The immune system undergoes changes as people age, and the speed of this process varies from patient to patient, which means immune age can be different from chronological age, said Dr. Bottomley. “We’re still exploring why immune aging should predispose you to cSCC,” he said.
 

When to Intervene?

Transplant patients are followed by dermatologists at regular intervals. But guidelines are not consistent on the recommended timing of those intervals.

Dr. Arron and colleagues in 2019 created a risk prediction module that recommended frequency of follow-up based on low, medium, high, or very high risk. The tool is available to clinicians in an app called SUNTRAC, or the Skin and Ultraviolet Neoplasia Transplant Risk Assessment Calculator.

A question that Dr. Arron said dermatologists and transplant specialists have wrangled with: How early can they intervene to prevent further lesions?

In the 2022 decision framework paper in Transplant International, Dr. Bottomley and dermatology colleagues from around the world attempted to better delineate when and how clinicians should intervene when a cSCC is first detected. That first cSCC “should be regarded as a ‘red flag’ heralding an increased risk of further skin cancers and possibly internal malignancies,” the authors wrote. That moment is “a key opportunity to proactively consider secondary preventive strategies,” they wrote, but noted that the best interventions and “their sequencing remain unclear,” indicating the need for further research.
 

Coordinating With the Transplant Team

A key strategy to help prevent cSCC development — suggested in Dr. Bottomley’s paper, and by Dr. Arron and Dr. Christensen — is to consult with the transplant team on potentially changing a patient’s immunosuppressive medication or reducing the dose.

Dr. Arron said that a decade ago, it was somewhat of a novel concept, requiring data-sharing and making personal connections with the transplant team to forge trusting relationships. By the time she left UCSF a few years ago, she said, “the transplant program was very much on board with preventing and treating skin cancer and oftentimes they were making changes even before I would suggest them.”

Suggesting a change or dose reduction is not undertaken lightly. “Our transplant physician colleagues are balancing multiple problems in very sick patients, of which skin cancer might be one, but not the most pressing one in the setting of other transplant complications,” said Dr. Arron.

Dr. Bottomley said that “as transplant physicians, we very much respect and value the input of our dermatology colleagues,” but agreed that many factors “outside malignancy risk” must be weighed when considering changing an immunosuppressive regimen.

In a Delphi Consensus Statement on prevention of cSCC in organ transplant recipients, published in 2021 in JAMA Dermatology, the authors recommended having discussions about immunosuppression with transplant specialists, but did not make a recommendation on what strategy to use. The consensus panel said it preferred “to defer this decision to transplant physicians.”

Acitretin a Go, Nicotinamide Not So Much

Outside of changing an immunosuppressive regimen, among the interventions for secondary prevention are acitretin, the systemic retinoid, and nicotinamide, a form of niacin.

Dr. Christensen conducted a small retrospective investigation evaluating the effectiveness of acitretin in reducing cSCC in both immunocompromised and immunocompetent patients who had received care at Yale, which was recently published in the Journal of the American Academy of Dermatology. Acitretin reduced invasive cSCC by about 75% in both patient groups — a surprising result for the immunocompetent group, but well-established in patients who have had a solid organ transplant. But acitretin had no effect on cSCC in situ or basal cell carcinoma. “The benefit of acitretin is primarily in preventing the invasive SCC,” said Dr. Christensen, which is why he tends to reserve it for patients who have already had several cSCCs.

“It’s not a completely benign medication,” he said, noting the need for monitoring for cholesterol and liver function.

Several years ago, a study in immunocompetent patients, published in the New England Journal of Medicine, found that nicotinamide (also known as niacinamide) reduced the rate of nonmelonoma skin cancer by 23%, giving clinicians hope that it might also be a low-risk, low-cost cancer preventive for solid organ transplant patients. But enthusiasm has dampened since a 2023 study in the New England Journal of Medicine found that the vitamin did not reduce cSCCs in transplant recipients.

Dr. Christensen said he believes the most-recent study wasn’t powered to detect a 25% reduction in cancers. “It’s certainly possible that it still works exactly the same way in transplant patients that it does in immunocompetent patients,” he said. “There’s very little risk of recommending it to patients for general prevention. But it probably has a very modest effect in many,” he said.

Dr. Arron agreed, saying, “it may be that we simply need bigger studies to achieve that statistical significance.” Even so, she said she would not use the therapy “until there is more evidence supporting the use of nicotinamide in transplant recipients.”

Immune checkpoint inhibitors such as cemiplimab and pembrolizumab have been approved by the US Food and Drug Administration for advanced cSCC; nivolumab is another drug in the same class that has not yet been approved for cSCC. But “there’s always been a fear — and a legitimate fear — that if you gave those to organ transplant recipients they would reject their organ,” said Dr. Christensen.

Patients who take the checkpoint inhibitors may first have to stop taking their antirejection drugs, leaving them at risk. It also appears that the checkpoint inhibitors themselves contribute to organ rejection. Recent studies suggest that “the rate of organ rejection is only about 30% to 40%,” with the checkpoint inhibitors, said Dr. Christensen. “Obviously that’s still not an ideal outcome,” he said, but noted that with patients who have inoperable metastatic cSCC, “immune therapy can be a good option.”

Dr. Christensen reported no disclosures. Dr. Bottomley has previously received speaker fees and an educational grant from Astellas. Dr. Arron disclosed ties with Regeneron, Castle Biosciences, and Enspectra Health, not specific to transplantation.

The patient had an advanced cutaneous squamous cell carcinoma (cSCC) on the face that seemed to be affecting the facial nerve, ruling out aggressive surgery. When Mohs surgery failed to clear the tumor, radiation was ordered. But the best option — an immune checkpoint inhibitor — could not be administered because the patient was a lung transplant recipient.

Although approved for metastatic cSCC, immune checkpoint inhibitors are associated with a higher potential for rejection of an organ transplant.

“The feeling is that the risk of rejection is just too great if we were to try to give an immune checkpoint inhibitor,” said Sean Christensen, MD, PhD, director of dermatologic surgery at Yale Dermatology–Branford, in Connecticut, who was treating the patient. Dr. Christensen consulted with the transplant team, and together they decided to switch the patient to sirolimus, an immunosuppressant that has been shown to have less risk of promoting skin cancer in those who take the medication. Sirolimus, however, is not as well tolerated as the usual first-line immunosuppressant, tacrolimus.

Dr. Christensen

Dr. Bottomley

Reducing Risk Factors

Dr. Bottomley said that there’s also been renewed effort to identify how to reduce cSCC risk in transplant recipients through recently developed consensus guidelines and a proposed decision framework developed by Dr. Bottomley and colleagues. The evidence will help clinicians have “greater confidence in making early interventions,” he said.

Currently, solid organ transplant patients are told to reduce sun exposure, in part because the majority of cSCCs occur in sun-exposed areas, such as the head and neck, and ultraviolet radiation leads to mutations. “Sun protection is critical,” Dr. Christensen said. That’s especially true in younger transplant recipients, who may have decades of sun exposure, he said.

The immunosuppressive medications also increase cancer risk, for a variety of reasons. One of the more-commonly used immunosuppressants in the past, azathioprine, is itself carcinogenic. Other antirejection medications, such as tacrolimus and mycophenolate, may also induce mutagenic changes that give rise to malignancies, according to the paper by Dr. Bibee, assistant professor of dermatology at Johns Hopkins, Baltimore.

Both Dr. Bibee, in her paper, and Dr. Arron, in an interview, noted that voriconazole, an antifungal used to prevent Aspergillus infection after lung transplant, has been associated with an increase in cSCC in lung transplant recipients.

Dr. Arron

In addition, immunosuppression essentially “blocks the body’s immune system from recognizing that there are abnormal cancerous cells present,” Dr. Arron, a dermatologist in private practice in Burlingame, California, told this news organization.

Previously, while at the High-Risk Skin Cancer Program at University of California, San Francisco (UCSF), Dr. Arron and others studied whether human papillomavirus (HPV) might play a role in spurring the development of cSCC formation in the immunocompromised. HPV is highly prevalent on the skin, but the virus found on the skin tends to be composed of lower-risk strains.

“In our research, we did not find any biologic mechanism by which this virus might be driving these cancers,” said Dr. Arron, although she said that some researchers “feel very strongly that HPV must be in some way a driver.”

Dr. Bottomley believes that HPV’s role has not been completely determined. The excess incidence of cSCC suggests a virus might be involved, as has been seen with excess risk of lymphoma in patients with Epstein-Barr virus, he said.

Some of his research is focusing on whether advanced immune aging is an independent risk factor for subsequent cSCC development in solid organ transplant recipients. The immune system undergoes changes as people age, and the speed of this process varies from patient to patient, which means immune age can be different from chronological age, said Dr. Bottomley. “We’re still exploring why immune aging should predispose you to cSCC,” he said.
 

When to Intervene?

Transplant patients are followed by dermatologists at regular intervals. But guidelines are not consistent on the recommended timing of those intervals.

Dr. Arron and colleagues in 2019 created a risk prediction module that recommended frequency of follow-up based on low, medium, high, or very high risk. The tool is available to clinicians in an app called SUNTRAC, or the Skin and Ultraviolet Neoplasia Transplant Risk Assessment Calculator.

A question that Dr. Arron said dermatologists and transplant specialists have wrangled with: How early can they intervene to prevent further lesions?

In the 2022 decision framework paper in Transplant International, Dr. Bottomley and dermatology colleagues from around the world attempted to better delineate when and how clinicians should intervene when a cSCC is first detected. That first cSCC “should be regarded as a ‘red flag’ heralding an increased risk of further skin cancers and possibly internal malignancies,” the authors wrote. That moment is “a key opportunity to proactively consider secondary preventive strategies,” they wrote, but noted that the best interventions and “their sequencing remain unclear,” indicating the need for further research.
 

Coordinating With the Transplant Team

A key strategy to help prevent cSCC development — suggested in Dr. Bottomley’s paper, and by Dr. Arron and Dr. Christensen — is to consult with the transplant team on potentially changing a patient’s immunosuppressive medication or reducing the dose.

Dr. Arron said that a decade ago, it was somewhat of a novel concept, requiring data-sharing and making personal connections with the transplant team to forge trusting relationships. By the time she left UCSF a few years ago, she said, “the transplant program was very much on board with preventing and treating skin cancer and oftentimes they were making changes even before I would suggest them.”

Suggesting a change or dose reduction is not undertaken lightly. “Our transplant physician colleagues are balancing multiple problems in very sick patients, of which skin cancer might be one, but not the most pressing one in the setting of other transplant complications,” said Dr. Arron.

Dr. Bottomley said that “as transplant physicians, we very much respect and value the input of our dermatology colleagues,” but agreed that many factors “outside malignancy risk” must be weighed when considering changing an immunosuppressive regimen.

In a Delphi Consensus Statement on prevention of cSCC in organ transplant recipients, published in 2021 in JAMA Dermatology, the authors recommended having discussions about immunosuppression with transplant specialists, but did not make a recommendation on what strategy to use. The consensus panel said it preferred “to defer this decision to transplant physicians.”

Acitretin a Go, Nicotinamide Not So Much

Outside of changing an immunosuppressive regimen, among the interventions for secondary prevention are acitretin, the systemic retinoid, and nicotinamide, a form of niacin.

Dr. Christensen conducted a small retrospective investigation evaluating the effectiveness of acitretin in reducing cSCC in both immunocompromised and immunocompetent patients who had received care at Yale, which was recently published in the Journal of the American Academy of Dermatology. Acitretin reduced invasive cSCC by about 75% in both patient groups — a surprising result for the immunocompetent group, but well-established in patients who have had a solid organ transplant. But acitretin had no effect on cSCC in situ or basal cell carcinoma. “The benefit of acitretin is primarily in preventing the invasive SCC,” said Dr. Christensen, which is why he tends to reserve it for patients who have already had several cSCCs.

“It’s not a completely benign medication,” he said, noting the need for monitoring for cholesterol and liver function.

Several years ago, a study in immunocompetent patients, published in the New England Journal of Medicine, found that nicotinamide (also known as niacinamide) reduced the rate of nonmelonoma skin cancer by 23%, giving clinicians hope that it might also be a low-risk, low-cost cancer preventive for solid organ transplant patients. But enthusiasm has dampened since a 2023 study in the New England Journal of Medicine found that the vitamin did not reduce cSCCs in transplant recipients.

Dr. Christensen said he believes the most-recent study wasn’t powered to detect a 25% reduction in cancers. “It’s certainly possible that it still works exactly the same way in transplant patients that it does in immunocompetent patients,” he said. “There’s very little risk of recommending it to patients for general prevention. But it probably has a very modest effect in many,” he said.

Dr. Arron agreed, saying, “it may be that we simply need bigger studies to achieve that statistical significance.” Even so, she said she would not use the therapy “until there is more evidence supporting the use of nicotinamide in transplant recipients.”

Immune checkpoint inhibitors such as cemiplimab and pembrolizumab have been approved by the US Food and Drug Administration for advanced cSCC; nivolumab is another drug in the same class that has not yet been approved for cSCC. But “there’s always been a fear — and a legitimate fear — that if you gave those to organ transplant recipients they would reject their organ,” said Dr. Christensen.

Patients who take the checkpoint inhibitors may first have to stop taking their antirejection drugs, leaving them at risk. It also appears that the checkpoint inhibitors themselves contribute to organ rejection. Recent studies suggest that “the rate of organ rejection is only about 30% to 40%,” with the checkpoint inhibitors, said Dr. Christensen. “Obviously that’s still not an ideal outcome,” he said, but noted that with patients who have inoperable metastatic cSCC, “immune therapy can be a good option.”

Dr. Christensen reported no disclosures. Dr. Bottomley has previously received speaker fees and an educational grant from Astellas. Dr. Arron disclosed ties with Regeneron, Castle Biosciences, and Enspectra Health, not specific to transplantation.

To the Editor:

Angioimmunoblastic T-cell lymphoma (AITL) is an uncommon peripheral T-cell lymphoma that accounts for 1% to 2% of all forms of non-Hodgkin lymphoma and usually affects middle-aged individuals.¹ It primarily appears on the skin and mimics an inflammatory dermatosis, leading to diagnostic and therapeutic delays.² No gold-standard treatment has been identified for AITL; the prognosis often remains poor, with a 5-year progression-free survival rate of approximately 25%.³ Because of the rarity of AITL and the unmet need of a standard-of-care treatment regimen, relapsing and remitting disease is common and continues to challenge clinicians.

Methotrexate (MTX), a dihydrofolate reductase inhibitor used to treat many autoimmune diseases, is prescribed at a higher dosage (>500 mg/m²) to manage cancers, including refractory AITL.⁴ In blocking dihydrofolate reductase, MTX reduces the folate pool, with the possible adverse effect of bone marrow suppression. Another important toxic effect is acute kidney injury, which may be due to an overdose of MTX or a patient’s predisposition to chronic kidney failure.⁴

A 50-year-old man was admitted to our inpatient clinic for evaluation of acute oral and genital mucositis. He had a 5-year history of AITL. He was previously treated by hematology with 3 lines of chemotherapy for multiple supradiaphragmatic and subdiaphragmatic localizations of lymphoma, without success. Six days prior to the current presentation, the hematologist started high-dose (3.5 g/m²) intravenous MTX therapy. Five days later, the patient developed transfusion-resistant pancytopenia and fever (maximum body temperature, 102.7°F [39.3°C]).

Physical examination at the current presentation revealed massive necrosis of the lower lip (Figure, A) and partial necrosis of the upper lip. Severe purulent balanoposthitis, causing penile edema and phimosis, complicated the clinical condition. Analysis of a specimen from a cutaneous swab of the penis showed infection with Pseudomonas aeruginosa and Enterococcus faecalis. Considering the clinical presentation and time of onset of signs and symptoms, a diagnosis of acute MTX-induced mucositis was made.

Rescue therapy was started immediately, including high-dose intravenous leucovorin (120 mg 4 times daily), oral sulfamethoxazole-trimethoprim (800 mg/160 mg 3 times daily for 3 days per week), and oral levofloxacin (500 mg/d). After 4 days of treatment, the patient was afebrile. Mucositis of the lips had almost resolved (Figure, B), and balanoposthitis also improved after this rescue therapy. Methotrexate was not resumed because rituximab had been started.

To the Editor:

Angioimmunoblastic T-cell lymphoma (AITL) is an uncommon peripheral T-cell lymphoma that accounts for 1% to 2% of all forms of non-Hodgkin lymphoma and usually affects middle-aged individuals.¹ It primarily appears on the skin and mimics an inflammatory dermatosis, leading to diagnostic and therapeutic delays.² No gold-standard treatment has been identified for AITL; the prognosis often remains poor, with a 5-year progression-free survival rate of approximately 25%.³ Because of the rarity of AITL and the unmet need of a standard-of-care treatment regimen, relapsing and remitting disease is common and continues to challenge clinicians.

Methotrexate (MTX), a dihydrofolate reductase inhibitor used to treat many autoimmune diseases, is prescribed at a higher dosage (>500 mg/m²) to manage cancers, including refractory AITL.⁴ In blocking dihydrofolate reductase, MTX reduces the folate pool, with the possible adverse effect of bone marrow suppression. Another important toxic effect is acute kidney injury, which may be due to an overdose of MTX or a patient’s predisposition to chronic kidney failure.⁴

A 50-year-old man was admitted to our inpatient clinic for evaluation of acute oral and genital mucositis. He had a 5-year history of AITL. He was previously treated by hematology with 3 lines of chemotherapy for multiple supradiaphragmatic and subdiaphragmatic localizations of lymphoma, without success. Six days prior to the current presentation, the hematologist started high-dose (3.5 g/m²) intravenous MTX therapy. Five days later, the patient developed transfusion-resistant pancytopenia and fever (maximum body temperature, 102.7°F [39.3°C]).

Physical examination at the current presentation revealed massive necrosis of the lower lip (Figure, A) and partial necrosis of the upper lip. Severe purulent balanoposthitis, causing penile edema and phimosis, complicated the clinical condition. Analysis of a specimen from a cutaneous swab of the penis showed infection with Pseudomonas aeruginosa and Enterococcus faecalis. Considering the clinical presentation and time of onset of signs and symptoms, a diagnosis of acute MTX-induced mucositis was made.

Rescue therapy was started immediately, including high-dose intravenous leucovorin (120 mg 4 times daily), oral sulfamethoxazole-trimethoprim (800 mg/160 mg 3 times daily for 3 days per week), and oral levofloxacin (500 mg/d). After 4 days of treatment, the patient was afebrile. Mucositis of the lips had almost resolved (Figure, B), and balanoposthitis also improved after this rescue therapy. Methotrexate was not resumed because rituximab had been started.

To the Editor:

Angioimmunoblastic T-cell lymphoma (AITL) is an uncommon peripheral T-cell lymphoma that accounts for 1% to 2% of all forms of non-Hodgkin lymphoma and usually affects middle-aged individuals.¹ It primarily appears on the skin and mimics an inflammatory dermatosis, leading to diagnostic and therapeutic delays.² No gold-standard treatment has been identified for AITL; the prognosis often remains poor, with a 5-year progression-free survival rate of approximately 25%.³ Because of the rarity of AITL and the unmet need of a standard-of-care treatment regimen, relapsing and remitting disease is common and continues to challenge clinicians.

Methotrexate (MTX), a dihydrofolate reductase inhibitor used to treat many autoimmune diseases, is prescribed at a higher dosage (>500 mg/m²) to manage cancers, including refractory AITL.⁴ In blocking dihydrofolate reductase, MTX reduces the folate pool, with the possible adverse effect of bone marrow suppression. Another important toxic effect is acute kidney injury, which may be due to an overdose of MTX or a patient’s predisposition to chronic kidney failure.⁴

A 50-year-old man was admitted to our inpatient clinic for evaluation of acute oral and genital mucositis. He had a 5-year history of AITL. He was previously treated by hematology with 3 lines of chemotherapy for multiple supradiaphragmatic and subdiaphragmatic localizations of lymphoma, without success. Six days prior to the current presentation, the hematologist started high-dose (3.5 g/m²) intravenous MTX therapy. Five days later, the patient developed transfusion-resistant pancytopenia and fever (maximum body temperature, 102.7°F [39.3°C]).

Physical examination at the current presentation revealed massive necrosis of the lower lip (Figure, A) and partial necrosis of the upper lip. Severe purulent balanoposthitis, causing penile edema and phimosis, complicated the clinical condition. Analysis of a specimen from a cutaneous swab of the penis showed infection with Pseudomonas aeruginosa and Enterococcus faecalis. Considering the clinical presentation and time of onset of signs and symptoms, a diagnosis of acute MTX-induced mucositis was made.

Rescue therapy was started immediately, including high-dose intravenous leucovorin (120 mg 4 times daily), oral sulfamethoxazole-trimethoprim (800 mg/160 mg 3 times daily for 3 days per week), and oral levofloxacin (500 mg/d). After 4 days of treatment, the patient was afebrile. Mucositis of the lips had almost resolved (Figure, B), and balanoposthitis also improved after this rescue therapy. Methotrexate was not resumed because rituximab had been started.

In April 2023, the US Preventive Services Task Force (USPSTF) issued a controversial recommendation that the current evidence is insufficient to assess the benefits vs harms of visual skin examination by clinicians for skin cancer screening in adolescents and adults who do not have signs or symptoms of skin cancer.^1,2 This recommendation by the USPSTF has not changed in a quarter century,³ but a recent study described an interesting paradox that should trigger wide evaluation and debate.

Patel et al⁴ analyzed data from the National Cancer Institute’s Surveillance, Epidemiology, and End Results Program from January 2000 to December 2018 to identify adults with a diagnosis of first primary melanoma in situ (MIS). Overall mortality was then determined through the National Vital Statistics System, which provides cause-of-death information for all deaths in the United States. The authors found 137,872 patients who had 1—and only 1—MIS discovered over the observation period. These patients predominantly were White (96.7%), and the mean (SD) age at diagnosis was 61.9 (16.5) years. During 910,308 total person-years of follow-up (mean [SD], 6.6 [5.1] years), 893 (0.6%) patients died of melanoma and 17,327 (12.6%) died of any cause. The 15-year melanoma-specific standardized mortality rate (SMR) was 1.89 (95% CI, 1.77-2.02), yet the 15-year overall survival relative to matched population controls was 112.4% (95% CI, 112.0%-112.8%), thus all-cause SMR was significantly lower at 0.68 (95% CI, 0.67-0.7). Although MIS was associated with a small increase in cohort melanoma mortality, overall mortality was actually lower than in the general population.⁴

Patel et al⁴ did a further broader search that included an additional 18,379 patients who also experienced a second primary melanoma, of which 6751 (36.7%) were invasive and 11,628 (63.3%) were in situ, with a melanoma-specific survival of 98.2% (95% CI, 97.6%-98.5%). Yet relative all-cause survival was significantly higher at 126.7% (95% CI, 125.5%-128.0%). Even among patients in whom a second primary melanoma was invasive, melanoma-specific survival was reduced to 91.1% (95% CI, 90.0%-92.1%), but relative all-cause survival was 116.7% (95% CI, 115%-118.4%). These data in the overall cohort of 155,251 patients showed a discordance between melanoma mortality, which was 4.27-times higher than in the general population (SMR, 4.27; 95% CI, 4.07-4.48), and a lower risk for death from all causes that was approximately 27% lower than in the general population (SMR, 0.73; 95% CI, 0.72-0.74). The authors showed that their findings were not associated with socioeconomic status.⁴

The analysis by Patel et al⁴ is now the second study in the literature to show this discordant melanoma survival pattern. In an earlier Australian study of 2452 melanoma patients, Watts et al⁵ reported that melanoma detection during routine skin checks was associated with a 25% lower all-cause mortality (hazard ratio, 0.75; 95% CI, 0.63-0.90) but not melanoma-specific mortality after multivariable adjustment for a variety of factors including socioeconomic status.These analyses by 2 different groups of investigators have broad implications. Both groups suggested that the improved life span in melanoma patients may be due to health-seeking behavior, which has been defined as “any action undertaken by individuals who perceive themselves to have a health problem or to be ill for the purpose of finding an appropriate remedy.”⁶

Once treated for melanoma, it is clear that patients are likely to return at regular intervals for thorough full-body skin examinations, but this activity alone could not be responsible for improved all-cause mortality in the face of increased melanoma-specific mortality. It seems the authors are implying a broader concept of good health behavior, originally defined by MacKian⁷ as encompassing “activities undertaken to maintain good health, to prevent ill health, as well as dealing with any departure from a good state of health,” such as overt behavioral patterns, actions, and habits with the goal of maintenance, restoration, and improvement of one’s health. A variety of behaviors fall within such a definition including smoking cessation, decreased alcohol use, good diet, more physical activity, safe sexual behavior, scheduling physician visits, medication adherence, vaccination, and yes—screening examinations for health problems.⁸

The concept that individuals who are diagnosed with melanoma fall into a pattern of good health behavior is an interesting hypothesis that must remain speculative until the multiple aspects of good health behavior are rigorously studied. This concept coexists with the hypothesis of melanoma “overdiagnosis”—the idea that many melanomas are detected that will never lead to death.⁹ Both concepts deserve further analysis. Unquestionably, a randomized controlled trial could never recruit patients willing to undergo long-term untreated observation of their melanomas to test the hypothesis that their melanoma diagnosis would eventually lead to death. Furthermore, Patel et al⁴ do suggest that even MIS carries a small but measurable increased risk for death from the disease, which is not particularly supportive of the overdiagnosis hypothesis; however, analysis of the concept that improved individual health behavior is at least in part responsible for the first discovery of melanomas is certainly approachable. Here is the key question: Did the melanoma diagnosis trigger a sudden change in multiple aspects of health behavior that led to significant all-cause mortality benefits? The average age of the population studied by Patel et al⁴ was approximately 62 years. One wonders whether the consequences of a lifetime of established health behavior patterns can be rapidly ­modified—certainly possible but again remains to be proven by further studies.

Conversely, the alternative hypothesis is that discovery of MIS was the result of active pursuit of self-examination and screening procedures as part of individually ingrained good health behavior over a lifetime. Goodwin et al¹⁰ carried out a study in a sample of the Medicare population aged 69 to 90 years looking at men who had prostate cancer screening via prostate-specific antigen measurement and women who had undergone mammography in older age, compared to the contrast population who had not had these screening procedures. They tracked date of death in Medicare enrollment files. They identified 543,970 women and 362,753 men who were aged 69 to 90 years as of January 1, 2003. Patients were stratified by life expectancy based on age and comorbidity. Within each stratum, the patients with cancer screening had higher actual median survival than those who were not screened, with differences ranging from 1.7 to 2.1 years for women and 0.9 to 1.1 years for men.¹⁰ These results were not the result of lower prostate or breast cancer mortality. Rather, one surmises that other health factors yielded lower mortality in the screened cohorts.

A full-body skin examination is a time-consuming process. Patients who come to their physician for a routine annual physical don’t expect a skin examination and very few physicians have the time for a long detailed full-body skin examination. When the patient presents to a dermatologist for an examination, it often is because they have real concerns; for example, they may have had a family member who died of skin cancer, or the patient themself may have noticed a worrisome lesion. Patients, not physicians, are the drivers of skin cancer screening, a fact that often is dismissed by those who are not necessarily supportive of the practice.

In light of the findings of Patel et al,⁴ it is essential that the USPSTF reviews be reanalyzed to compare skin cancer–specific mortality, all-cause mortality, and lifespan in individuals who pursue skin cancer screening; the reanalysis also should not be exclusively limited to survival. With the advent of the immune checkpoint inhibitors, patients with metastatic melanoma are living much longer.¹¹ The burden of living with metastatic cancer must be characterized and measured to have a complete picture and a valid analysis.

After the release of the USPSTF recommendation, there have been calls for large-scale studies to prove the benefits of skin cancer screening.¹² Such studies may be valuable; however, if the hypothesis that overall healthy behavior as the major outcome determinant is substantiated, it may prove quite challenging to perform tests of association with specific interventions. It has been shown that skin cancer screening does lead to discovery of more melanomas,¹³ yet in light of the paradox described by Patel et al,⁴ it also is likely that causes of death other than melanoma impact overall mortality. Patients who pursue skin examinations may engage in multiple different health activities that are beneficial in the long term, making it difficult to analyze the specific benefit of skin cancer screening in isolation. It may prove difficult to ask patients to omit selected aspects of healthy behavior to try to prove the point. At this time, there is much more work to be done prior to offering opinions on the importance of skin cancer examination in isolation to improve overall health care. In the meantime, dermatologists owe it to our patients to continue to diligently pursue thorough and detailed skin examinations.

In April 2023, the US Preventive Services Task Force (USPSTF) issued a controversial recommendation that the current evidence is insufficient to assess the benefits vs harms of visual skin examination by clinicians for skin cancer screening in adolescents and adults who do not have signs or symptoms of skin cancer.^1,2 This recommendation by the USPSTF has not changed in a quarter century,³ but a recent study described an interesting paradox that should trigger wide evaluation and debate.

Patel et al⁴ analyzed data from the National Cancer Institute’s Surveillance, Epidemiology, and End Results Program from January 2000 to December 2018 to identify adults with a diagnosis of first primary melanoma in situ (MIS). Overall mortality was then determined through the National Vital Statistics System, which provides cause-of-death information for all deaths in the United States. The authors found 137,872 patients who had 1—and only 1—MIS discovered over the observation period. These patients predominantly were White (96.7%), and the mean (SD) age at diagnosis was 61.9 (16.5) years. During 910,308 total person-years of follow-up (mean [SD], 6.6 [5.1] years), 893 (0.6%) patients died of melanoma and 17,327 (12.6%) died of any cause. The 15-year melanoma-specific standardized mortality rate (SMR) was 1.89 (95% CI, 1.77-2.02), yet the 15-year overall survival relative to matched population controls was 112.4% (95% CI, 112.0%-112.8%), thus all-cause SMR was significantly lower at 0.68 (95% CI, 0.67-0.7). Although MIS was associated with a small increase in cohort melanoma mortality, overall mortality was actually lower than in the general population.⁴

Patel et al⁴ did a further broader search that included an additional 18,379 patients who also experienced a second primary melanoma, of which 6751 (36.7%) were invasive and 11,628 (63.3%) were in situ, with a melanoma-specific survival of 98.2% (95% CI, 97.6%-98.5%). Yet relative all-cause survival was significantly higher at 126.7% (95% CI, 125.5%-128.0%). Even among patients in whom a second primary melanoma was invasive, melanoma-specific survival was reduced to 91.1% (95% CI, 90.0%-92.1%), but relative all-cause survival was 116.7% (95% CI, 115%-118.4%). These data in the overall cohort of 155,251 patients showed a discordance between melanoma mortality, which was 4.27-times higher than in the general population (SMR, 4.27; 95% CI, 4.07-4.48), and a lower risk for death from all causes that was approximately 27% lower than in the general population (SMR, 0.73; 95% CI, 0.72-0.74). The authors showed that their findings were not associated with socioeconomic status.⁴

The analysis by Patel et al⁴ is now the second study in the literature to show this discordant melanoma survival pattern. In an earlier Australian study of 2452 melanoma patients, Watts et al⁵ reported that melanoma detection during routine skin checks was associated with a 25% lower all-cause mortality (hazard ratio, 0.75; 95% CI, 0.63-0.90) but not melanoma-specific mortality after multivariable adjustment for a variety of factors including socioeconomic status.These analyses by 2 different groups of investigators have broad implications. Both groups suggested that the improved life span in melanoma patients may be due to health-seeking behavior, which has been defined as “any action undertaken by individuals who perceive themselves to have a health problem or to be ill for the purpose of finding an appropriate remedy.”⁶

Once treated for melanoma, it is clear that patients are likely to return at regular intervals for thorough full-body skin examinations, but this activity alone could not be responsible for improved all-cause mortality in the face of increased melanoma-specific mortality. It seems the authors are implying a broader concept of good health behavior, originally defined by MacKian⁷ as encompassing “activities undertaken to maintain good health, to prevent ill health, as well as dealing with any departure from a good state of health,” such as overt behavioral patterns, actions, and habits with the goal of maintenance, restoration, and improvement of one’s health. A variety of behaviors fall within such a definition including smoking cessation, decreased alcohol use, good diet, more physical activity, safe sexual behavior, scheduling physician visits, medication adherence, vaccination, and yes—screening examinations for health problems.⁸

The concept that individuals who are diagnosed with melanoma fall into a pattern of good health behavior is an interesting hypothesis that must remain speculative until the multiple aspects of good health behavior are rigorously studied. This concept coexists with the hypothesis of melanoma “overdiagnosis”—the idea that many melanomas are detected that will never lead to death.⁹ Both concepts deserve further analysis. Unquestionably, a randomized controlled trial could never recruit patients willing to undergo long-term untreated observation of their melanomas to test the hypothesis that their melanoma diagnosis would eventually lead to death. Furthermore, Patel et al⁴ do suggest that even MIS carries a small but measurable increased risk for death from the disease, which is not particularly supportive of the overdiagnosis hypothesis; however, analysis of the concept that improved individual health behavior is at least in part responsible for the first discovery of melanomas is certainly approachable. Here is the key question: Did the melanoma diagnosis trigger a sudden change in multiple aspects of health behavior that led to significant all-cause mortality benefits? The average age of the population studied by Patel et al⁴ was approximately 62 years. One wonders whether the consequences of a lifetime of established health behavior patterns can be rapidly ­modified—certainly possible but again remains to be proven by further studies.

Conversely, the alternative hypothesis is that discovery of MIS was the result of active pursuit of self-examination and screening procedures as part of individually ingrained good health behavior over a lifetime. Goodwin et al¹⁰ carried out a study in a sample of the Medicare population aged 69 to 90 years looking at men who had prostate cancer screening via prostate-specific antigen measurement and women who had undergone mammography in older age, compared to the contrast population who had not had these screening procedures. They tracked date of death in Medicare enrollment files. They identified 543,970 women and 362,753 men who were aged 69 to 90 years as of January 1, 2003. Patients were stratified by life expectancy based on age and comorbidity. Within each stratum, the patients with cancer screening had higher actual median survival than those who were not screened, with differences ranging from 1.7 to 2.1 years for women and 0.9 to 1.1 years for men.¹⁰ These results were not the result of lower prostate or breast cancer mortality. Rather, one surmises that other health factors yielded lower mortality in the screened cohorts.

A full-body skin examination is a time-consuming process. Patients who come to their physician for a routine annual physical don’t expect a skin examination and very few physicians have the time for a long detailed full-body skin examination. When the patient presents to a dermatologist for an examination, it often is because they have real concerns; for example, they may have had a family member who died of skin cancer, or the patient themself may have noticed a worrisome lesion. Patients, not physicians, are the drivers of skin cancer screening, a fact that often is dismissed by those who are not necessarily supportive of the practice.

In light of the findings of Patel et al,⁴ it is essential that the USPSTF reviews be reanalyzed to compare skin cancer–specific mortality, all-cause mortality, and lifespan in individuals who pursue skin cancer screening; the reanalysis also should not be exclusively limited to survival. With the advent of the immune checkpoint inhibitors, patients with metastatic melanoma are living much longer.¹¹ The burden of living with metastatic cancer must be characterized and measured to have a complete picture and a valid analysis.

After the release of the USPSTF recommendation, there have been calls for large-scale studies to prove the benefits of skin cancer screening.¹² Such studies may be valuable; however, if the hypothesis that overall healthy behavior as the major outcome determinant is substantiated, it may prove quite challenging to perform tests of association with specific interventions. It has been shown that skin cancer screening does lead to discovery of more melanomas,¹³ yet in light of the paradox described by Patel et al,⁴ it also is likely that causes of death other than melanoma impact overall mortality. Patients who pursue skin examinations may engage in multiple different health activities that are beneficial in the long term, making it difficult to analyze the specific benefit of skin cancer screening in isolation. It may prove difficult to ask patients to omit selected aspects of healthy behavior to try to prove the point. At this time, there is much more work to be done prior to offering opinions on the importance of skin cancer examination in isolation to improve overall health care. In the meantime, dermatologists owe it to our patients to continue to diligently pursue thorough and detailed skin examinations.

In April 2023, the US Preventive Services Task Force (USPSTF) issued a controversial recommendation that the current evidence is insufficient to assess the benefits vs harms of visual skin examination by clinicians for skin cancer screening in adolescents and adults who do not have signs or symptoms of skin cancer.^1,2 This recommendation by the USPSTF has not changed in a quarter century,³ but a recent study described an interesting paradox that should trigger wide evaluation and debate.

Patel et al⁴ analyzed data from the National Cancer Institute’s Surveillance, Epidemiology, and End Results Program from January 2000 to December 2018 to identify adults with a diagnosis of first primary melanoma in situ (MIS). Overall mortality was then determined through the National Vital Statistics System, which provides cause-of-death information for all deaths in the United States. The authors found 137,872 patients who had 1—and only 1—MIS discovered over the observation period. These patients predominantly were White (96.7%), and the mean (SD) age at diagnosis was 61.9 (16.5) years. During 910,308 total person-years of follow-up (mean [SD], 6.6 [5.1] years), 893 (0.6%) patients died of melanoma and 17,327 (12.6%) died of any cause. The 15-year melanoma-specific standardized mortality rate (SMR) was 1.89 (95% CI, 1.77-2.02), yet the 15-year overall survival relative to matched population controls was 112.4% (95% CI, 112.0%-112.8%), thus all-cause SMR was significantly lower at 0.68 (95% CI, 0.67-0.7). Although MIS was associated with a small increase in cohort melanoma mortality, overall mortality was actually lower than in the general population.⁴

Patel et al⁴ did a further broader search that included an additional 18,379 patients who also experienced a second primary melanoma, of which 6751 (36.7%) were invasive and 11,628 (63.3%) were in situ, with a melanoma-specific survival of 98.2% (95% CI, 97.6%-98.5%). Yet relative all-cause survival was significantly higher at 126.7% (95% CI, 125.5%-128.0%). Even among patients in whom a second primary melanoma was invasive, melanoma-specific survival was reduced to 91.1% (95% CI, 90.0%-92.1%), but relative all-cause survival was 116.7% (95% CI, 115%-118.4%). These data in the overall cohort of 155,251 patients showed a discordance between melanoma mortality, which was 4.27-times higher than in the general population (SMR, 4.27; 95% CI, 4.07-4.48), and a lower risk for death from all causes that was approximately 27% lower than in the general population (SMR, 0.73; 95% CI, 0.72-0.74). The authors showed that their findings were not associated with socioeconomic status.⁴

The analysis by Patel et al⁴ is now the second study in the literature to show this discordant melanoma survival pattern. In an earlier Australian study of 2452 melanoma patients, Watts et al⁵ reported that melanoma detection during routine skin checks was associated with a 25% lower all-cause mortality (hazard ratio, 0.75; 95% CI, 0.63-0.90) but not melanoma-specific mortality after multivariable adjustment for a variety of factors including socioeconomic status.These analyses by 2 different groups of investigators have broad implications. Both groups suggested that the improved life span in melanoma patients may be due to health-seeking behavior, which has been defined as “any action undertaken by individuals who perceive themselves to have a health problem or to be ill for the purpose of finding an appropriate remedy.”⁶

Once treated for melanoma, it is clear that patients are likely to return at regular intervals for thorough full-body skin examinations, but this activity alone could not be responsible for improved all-cause mortality in the face of increased melanoma-specific mortality. It seems the authors are implying a broader concept of good health behavior, originally defined by MacKian⁷ as encompassing “activities undertaken to maintain good health, to prevent ill health, as well as dealing with any departure from a good state of health,” such as overt behavioral patterns, actions, and habits with the goal of maintenance, restoration, and improvement of one’s health. A variety of behaviors fall within such a definition including smoking cessation, decreased alcohol use, good diet, more physical activity, safe sexual behavior, scheduling physician visits, medication adherence, vaccination, and yes—screening examinations for health problems.⁸

The concept that individuals who are diagnosed with melanoma fall into a pattern of good health behavior is an interesting hypothesis that must remain speculative until the multiple aspects of good health behavior are rigorously studied. This concept coexists with the hypothesis of melanoma “overdiagnosis”—the idea that many melanomas are detected that will never lead to death.⁹ Both concepts deserve further analysis. Unquestionably, a randomized controlled trial could never recruit patients willing to undergo long-term untreated observation of their melanomas to test the hypothesis that their melanoma diagnosis would eventually lead to death. Furthermore, Patel et al⁴ do suggest that even MIS carries a small but measurable increased risk for death from the disease, which is not particularly supportive of the overdiagnosis hypothesis; however, analysis of the concept that improved individual health behavior is at least in part responsible for the first discovery of melanomas is certainly approachable. Here is the key question: Did the melanoma diagnosis trigger a sudden change in multiple aspects of health behavior that led to significant all-cause mortality benefits? The average age of the population studied by Patel et al⁴ was approximately 62 years. One wonders whether the consequences of a lifetime of established health behavior patterns can be rapidly ­modified—certainly possible but again remains to be proven by further studies.

Conversely, the alternative hypothesis is that discovery of MIS was the result of active pursuit of self-examination and screening procedures as part of individually ingrained good health behavior over a lifetime. Goodwin et al¹⁰ carried out a study in a sample of the Medicare population aged 69 to 90 years looking at men who had prostate cancer screening via prostate-specific antigen measurement and women who had undergone mammography in older age, compared to the contrast population who had not had these screening procedures. They tracked date of death in Medicare enrollment files. They identified 543,970 women and 362,753 men who were aged 69 to 90 years as of January 1, 2003. Patients were stratified by life expectancy based on age and comorbidity. Within each stratum, the patients with cancer screening had higher actual median survival than those who were not screened, with differences ranging from 1.7 to 2.1 years for women and 0.9 to 1.1 years for men.¹⁰ These results were not the result of lower prostate or breast cancer mortality. Rather, one surmises that other health factors yielded lower mortality in the screened cohorts.

A full-body skin examination is a time-consuming process. Patients who come to their physician for a routine annual physical don’t expect a skin examination and very few physicians have the time for a long detailed full-body skin examination. When the patient presents to a dermatologist for an examination, it often is because they have real concerns; for example, they may have had a family member who died of skin cancer, or the patient themself may have noticed a worrisome lesion. Patients, not physicians, are the drivers of skin cancer screening, a fact that often is dismissed by those who are not necessarily supportive of the practice.

In light of the findings of Patel et al,⁴ it is essential that the USPSTF reviews be reanalyzed to compare skin cancer–specific mortality, all-cause mortality, and lifespan in individuals who pursue skin cancer screening; the reanalysis also should not be exclusively limited to survival. With the advent of the immune checkpoint inhibitors, patients with metastatic melanoma are living much longer.¹¹ The burden of living with metastatic cancer must be characterized and measured to have a complete picture and a valid analysis.

After the release of the USPSTF recommendation, there have been calls for large-scale studies to prove the benefits of skin cancer screening.¹² Such studies may be valuable; however, if the hypothesis that overall healthy behavior as the major outcome determinant is substantiated, it may prove quite challenging to perform tests of association with specific interventions. It has been shown that skin cancer screening does lead to discovery of more melanomas,¹³ yet in light of the paradox described by Patel et al,⁴ it also is likely that causes of death other than melanoma impact overall mortality. Patients who pursue skin examinations may engage in multiple different health activities that are beneficial in the long term, making it difficult to analyze the specific benefit of skin cancer screening in isolation. It may prove difficult to ask patients to omit selected aspects of healthy behavior to try to prove the point. At this time, there is much more work to be done prior to offering opinions on the importance of skin cancer examination in isolation to improve overall health care. In the meantime, dermatologists owe it to our patients to continue to diligently pursue thorough and detailed skin examinations.

Officials at Dana-Farber Cancer Institute are moving to retract at least six published research papers and correct 31 others amid allegations of data manipulation.

News of the investigation follows a blog post by British molecular biologist Sholto David, MD, who flagged almost 60 papers published between 1997 and 2017 that contained image manipulation and other errors. Some of the papers were published by Dana-Farber’s chief executive officer, Laurie Glimcher, MD, and chief operating officer, William Hahn, MD, on topics including multiple myeloma and immune cells.

Mr. David, who blogs about research integrity, highlighted numerous errors and irregularities, including copying and pasting images across multiple experiments to represent different days within the same experiment, sometimes rotating or stretching images.

In one case, Mr. David equated the manipulation with tactics used by “hapless Chinese papermills” and concluded that “a swathe of research coming out of [Dana-Farber] authored by the most senior researchers and managers appears to be hopelessly corrupt with errors that are obvious from just a cursory reading the papers.” 

“Imagine what mistakes might be found in the raw data if anyone was allowed to look!” he wrote.

Barrett Rollins, MD, PhD, Dana-Farber Cancer Institute’s research integrity officer, declined to comment on whether the errors represent scientific misconduct, according to STAT. Rollins told ScienceInsider that the “presence of image discrepancies in a paper is not evidence of an author’s intent to deceive.” 

Access to new artificial intelligence tools is making it easier for data sleuths, like Mr. David, to unearth data manipulation and errors. 

The current investigation closely follows two other investigations into the published work of Harvard University’s former president, Claudine Gay, and Stanford University’s former president, Marc Tessier-Lavigne, which led both to resign their posts. 

A version of this article appeared on Medscape.com.

Officials at Dana-Farber Cancer Institute are moving to retract at least six published research papers and correct 31 others amid allegations of data manipulation.

News of the investigation follows a blog post by British molecular biologist Sholto David, MD, who flagged almost 60 papers published between 1997 and 2017 that contained image manipulation and other errors. Some of the papers were published by Dana-Farber’s chief executive officer, Laurie Glimcher, MD, and chief operating officer, William Hahn, MD, on topics including multiple myeloma and immune cells.

Mr. David, who blogs about research integrity, highlighted numerous errors and irregularities, including copying and pasting images across multiple experiments to represent different days within the same experiment, sometimes rotating or stretching images.

In one case, Mr. David equated the manipulation with tactics used by “hapless Chinese papermills” and concluded that “a swathe of research coming out of [Dana-Farber] authored by the most senior researchers and managers appears to be hopelessly corrupt with errors that are obvious from just a cursory reading the papers.” 

“Imagine what mistakes might be found in the raw data if anyone was allowed to look!” he wrote.

Barrett Rollins, MD, PhD, Dana-Farber Cancer Institute’s research integrity officer, declined to comment on whether the errors represent scientific misconduct, according to STAT. Rollins told ScienceInsider that the “presence of image discrepancies in a paper is not evidence of an author’s intent to deceive.” 

Access to new artificial intelligence tools is making it easier for data sleuths, like Mr. David, to unearth data manipulation and errors. 

The current investigation closely follows two other investigations into the published work of Harvard University’s former president, Claudine Gay, and Stanford University’s former president, Marc Tessier-Lavigne, which led both to resign their posts. 

A version of this article appeared on Medscape.com.

Officials at Dana-Farber Cancer Institute are moving to retract at least six published research papers and correct 31 others amid allegations of data manipulation.

News of the investigation follows a blog post by British molecular biologist Sholto David, MD, who flagged almost 60 papers published between 1997 and 2017 that contained image manipulation and other errors. Some of the papers were published by Dana-Farber’s chief executive officer, Laurie Glimcher, MD, and chief operating officer, William Hahn, MD, on topics including multiple myeloma and immune cells.

Mr. David, who blogs about research integrity, highlighted numerous errors and irregularities, including copying and pasting images across multiple experiments to represent different days within the same experiment, sometimes rotating or stretching images.

In one case, Mr. David equated the manipulation with tactics used by “hapless Chinese papermills” and concluded that “a swathe of research coming out of [Dana-Farber] authored by the most senior researchers and managers appears to be hopelessly corrupt with errors that are obvious from just a cursory reading the papers.” 

“Imagine what mistakes might be found in the raw data if anyone was allowed to look!” he wrote.

Barrett Rollins, MD, PhD, Dana-Farber Cancer Institute’s research integrity officer, declined to comment on whether the errors represent scientific misconduct, according to STAT. Rollins told ScienceInsider that the “presence of image discrepancies in a paper is not evidence of an author’s intent to deceive.” 

Access to new artificial intelligence tools is making it easier for data sleuths, like Mr. David, to unearth data manipulation and errors. 

The current investigation closely follows two other investigations into the published work of Harvard University’s former president, Claudine Gay, and Stanford University’s former president, Marc Tessier-Lavigne, which led both to resign their posts. 

A version of this article appeared on Medscape.com.

Radiation oncologists from the largest professional societies have come together to lobby for Medicare payment reform.

The American Society for Radiation Oncology (ASTRO) recently announced its partnership with three other groups — the American College of Radiation Oncology, the American College of Radiology, and the American Society of Clinical Oncology — to change how the specialty is paid for services. 

Over the past decade, radiation oncologists have seen a 23% drop in Medicare reimbursement for radiation therapy services, with more cuts to come, according to a press release from ASTRO.

Traditionally, Medicare has reimbursed on the basis of the fraction of radiation delivered. But with moves toward hypofractionated regimens, deescalated therapy, and other changes in the field, reimbursement has continued to dwindle. 

The cuts have led to practice consolidation and closures that threaten patient access especially in rural and underserved areas, a spokesperson for the group told this news organization.

To reverse this trend, ASTRO recently proposed the Radiation Oncology Case Rate program, a legislative initiative to base reimbursements on patient volumes instead of fractions delivered. 

ASTRO is currently drafting a congressional bill to change the current payment structure, which “has become untenable,” the spokesperson said. 

A version of this article appeared on Medscape.com.

Radiation oncologists from the largest professional societies have come together to lobby for Medicare payment reform.

The American Society for Radiation Oncology (ASTRO) recently announced its partnership with three other groups — the American College of Radiation Oncology, the American College of Radiology, and the American Society of Clinical Oncology — to change how the specialty is paid for services. 

Over the past decade, radiation oncologists have seen a 23% drop in Medicare reimbursement for radiation therapy services, with more cuts to come, according to a press release from ASTRO.

Traditionally, Medicare has reimbursed on the basis of the fraction of radiation delivered. But with moves toward hypofractionated regimens, deescalated therapy, and other changes in the field, reimbursement has continued to dwindle. 

The cuts have led to practice consolidation and closures that threaten patient access especially in rural and underserved areas, a spokesperson for the group told this news organization.

To reverse this trend, ASTRO recently proposed the Radiation Oncology Case Rate program, a legislative initiative to base reimbursements on patient volumes instead of fractions delivered. 

ASTRO is currently drafting a congressional bill to change the current payment structure, which “has become untenable,” the spokesperson said. 

A version of this article appeared on Medscape.com.

Radiation oncologists from the largest professional societies have come together to lobby for Medicare payment reform.

The American Society for Radiation Oncology (ASTRO) recently announced its partnership with three other groups — the American College of Radiation Oncology, the American College of Radiology, and the American Society of Clinical Oncology — to change how the specialty is paid for services. 

Over the past decade, radiation oncologists have seen a 23% drop in Medicare reimbursement for radiation therapy services, with more cuts to come, according to a press release from ASTRO.

Traditionally, Medicare has reimbursed on the basis of the fraction of radiation delivered. But with moves toward hypofractionated regimens, deescalated therapy, and other changes in the field, reimbursement has continued to dwindle. 

The cuts have led to practice consolidation and closures that threaten patient access especially in rural and underserved areas, a spokesperson for the group told this news organization.

To reverse this trend, ASTRO recently proposed the Radiation Oncology Case Rate program, a legislative initiative to base reimbursements on patient volumes instead of fractions delivered. 

ASTRO is currently drafting a congressional bill to change the current payment structure, which “has become untenable,” the spokesperson said. 

A version of this article appeared on Medscape.com.

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.