Nonmelanoma Skin Cancer

The Food and Drug Administration has approved cemiplimab-rwlc (Libtayo) as the first immunotherapy to treat patients with locally advanced or metastatic basal cell carcinoma (BCC) previously treated with a hedgehog pathway inhibitor or in whom an HHI is inappropriate.

The FDA granted full approval for the locally advanced BCC indication and accelerated approval for the metastatic BCC indication, according to a press release from Regeneron and Sanofi, the companies jointly developing cemiplimab.

Cemiplimab is a programmed death–1 inhibitor that was first FDA approved in 2018 for locally advanced or metastatic cutaneous squamous cell carcinoma not eligible for curative surgery or radiation.

The new approval “will change the treatment paradigm for patients with advanced basal cell carcinoma,” according to Karl Lewis, MD, a professor at the University of Colorado at Denver, Aurora, and an investigator on the phase 2 trial of cemiplimab.

“While the primary systemic treatment options are hedgehog inhibitors, many patients will eventually progress on or become intolerant to this therapy,” Dr. Lewis said in the press release. “With Libtayo [cemiplimab], these patients now have a new immunotherapy option.”

The approval of cemiplimab in BCC was based on an open-label, phase 2 trial of 132 patients with advanced BCC. Patients could not tolerate, had progressed on, or had not responded to HHIs after 9 months of treatment.

Cemiplimab was given at 350 mg every 3 weeks. The study was not placebo controlled and has not been published, a Regeneron spokesperson said.

There were 112 patients in the efficacy analysis. The overall response rate was 21% (6/28) in metastatic BCC patients, with no complete responders. In locally advanced BCC patients, the objective response rate was 29% (24/84), with five complete responders.

The median duration of response was not reached in either group but was at least 6 months long in all metastatic patients and in 79% (19/84) of the locally advanced BCC patients.

The most common adverse events among the 132 subjects evaluable for safety were fatigue (49%), musculoskeletal pain (33%), diarrhea (25%), rash (22%), pruritus (20%), and upper respiratory tract infection (15%).

Serious adverse events occurred in 32% of patients, including colitis, acute kidney injury, adrenal insufficiency, and anemia. Adverse events led to discontinuation in 13% of patients, most often for colitis and general physical health deterioration.

For more details on cemiplimab, see the full prescribing information.

[email protected]

The Food and Drug Administration has approved cemiplimab-rwlc (Libtayo) as the first immunotherapy to treat patients with locally advanced or metastatic basal cell carcinoma (BCC) previously treated with a hedgehog pathway inhibitor or in whom an HHI is inappropriate.

The FDA granted full approval for the locally advanced BCC indication and accelerated approval for the metastatic BCC indication, according to a press release from Regeneron and Sanofi, the companies jointly developing cemiplimab.

Cemiplimab is a programmed death–1 inhibitor that was first FDA approved in 2018 for locally advanced or metastatic cutaneous squamous cell carcinoma not eligible for curative surgery or radiation.

The new approval “will change the treatment paradigm for patients with advanced basal cell carcinoma,” according to Karl Lewis, MD, a professor at the University of Colorado at Denver, Aurora, and an investigator on the phase 2 trial of cemiplimab.

“While the primary systemic treatment options are hedgehog inhibitors, many patients will eventually progress on or become intolerant to this therapy,” Dr. Lewis said in the press release. “With Libtayo [cemiplimab], these patients now have a new immunotherapy option.”

The approval of cemiplimab in BCC was based on an open-label, phase 2 trial of 132 patients with advanced BCC. Patients could not tolerate, had progressed on, or had not responded to HHIs after 9 months of treatment.

Cemiplimab was given at 350 mg every 3 weeks. The study was not placebo controlled and has not been published, a Regeneron spokesperson said.

There were 112 patients in the efficacy analysis. The overall response rate was 21% (6/28) in metastatic BCC patients, with no complete responders. In locally advanced BCC patients, the objective response rate was 29% (24/84), with five complete responders.

The median duration of response was not reached in either group but was at least 6 months long in all metastatic patients and in 79% (19/84) of the locally advanced BCC patients.

The most common adverse events among the 132 subjects evaluable for safety were fatigue (49%), musculoskeletal pain (33%), diarrhea (25%), rash (22%), pruritus (20%), and upper respiratory tract infection (15%).

Serious adverse events occurred in 32% of patients, including colitis, acute kidney injury, adrenal insufficiency, and anemia. Adverse events led to discontinuation in 13% of patients, most often for colitis and general physical health deterioration.

For more details on cemiplimab, see the full prescribing information.

[email protected]

The Food and Drug Administration has approved cemiplimab-rwlc (Libtayo) as the first immunotherapy to treat patients with locally advanced or metastatic basal cell carcinoma (BCC) previously treated with a hedgehog pathway inhibitor or in whom an HHI is inappropriate.

The FDA granted full approval for the locally advanced BCC indication and accelerated approval for the metastatic BCC indication, according to a press release from Regeneron and Sanofi, the companies jointly developing cemiplimab.

Cemiplimab is a programmed death–1 inhibitor that was first FDA approved in 2018 for locally advanced or metastatic cutaneous squamous cell carcinoma not eligible for curative surgery or radiation.

The new approval “will change the treatment paradigm for patients with advanced basal cell carcinoma,” according to Karl Lewis, MD, a professor at the University of Colorado at Denver, Aurora, and an investigator on the phase 2 trial of cemiplimab.

“While the primary systemic treatment options are hedgehog inhibitors, many patients will eventually progress on or become intolerant to this therapy,” Dr. Lewis said in the press release. “With Libtayo [cemiplimab], these patients now have a new immunotherapy option.”

The approval of cemiplimab in BCC was based on an open-label, phase 2 trial of 132 patients with advanced BCC. Patients could not tolerate, had progressed on, or had not responded to HHIs after 9 months of treatment.

Cemiplimab was given at 350 mg every 3 weeks. The study was not placebo controlled and has not been published, a Regeneron spokesperson said.

There were 112 patients in the efficacy analysis. The overall response rate was 21% (6/28) in metastatic BCC patients, with no complete responders. In locally advanced BCC patients, the objective response rate was 29% (24/84), with five complete responders.

The median duration of response was not reached in either group but was at least 6 months long in all metastatic patients and in 79% (19/84) of the locally advanced BCC patients.

The most common adverse events among the 132 subjects evaluable for safety were fatigue (49%), musculoskeletal pain (33%), diarrhea (25%), rash (22%), pruritus (20%), and upper respiratory tract infection (15%).

Serious adverse events occurred in 32% of patients, including colitis, acute kidney injury, adrenal insufficiency, and anemia. Adverse events led to discontinuation in 13% of patients, most often for colitis and general physical health deterioration.

For more details on cemiplimab, see the full prescribing information.

[email protected]

Best practices for managing cancer outpatients continue to evolve during the COVID-19 pandemic, with recent innovations in technology, operations, and communication.

“We’ve tried a lot of new things to ensure optimal care for our patients,” said Tiffany A. Traina, MD, of Memorial Sloan Kettering Cancer Center (MSKCC) in New York. “We need to effectively utilize all resources at our disposal to keep in touch with our patients during this time.”

Dr. Traina described the approach to outpatient management used at MSKCC during a presentation at the AACR Virtual Meeting: COVID-19 and Cancer.
 

Four guiding principles

MSKCC has established four guiding principles on how to manage cancer patients during the pandemic: openness, safety, technology, and staffing.

Openness ensures that decisions are guided by clinical priorities to provide optimal patient care and allow for prioritization of clinical research and education, Dr. Traina said.

The safety of patients and staff is of the utmost importance, she added. To ensure safety in the context of outpatient care, several operational levers were developed, including COVID surge planning, universal masking and personal protective equipment guidelines, remote work, clinical levers, and new dashboards and communications.

Dr. Traina said data analytics and dashboards have been key technological tools used to support evidence-based decision-making and deliver care remotely for patients during the pandemic.

Staffing resources have also shifted to support demand at different health system locations.
 

Screening, cohorting, and telemedicine

One measure MSKCC adopted is the MSK Engage Questionnaire, a COVID-19 screening questionnaire assigned to every patient with a scheduled outpatient visit. After completing the questionnaire, patients receive a response denoting whether they need to come into the outpatient setting.

On the staffing side, clinic coordinators prepare appointments accordingly, based on the risk level for each patient.

“We also try to cohort COVID-positive patients into particular areas within the outpatient setting,” Dr. Traina explained. “In addition, we control flow through ambulatory care locations by having separate patient entrances and use other tools to make flow as efficient as possible.”

On the technology side, interactive dashboards are being used to model traffic through different buildings.

“These data and analytics are useful for operational engineering, answering questions such as (1) Are there backups in chemotherapy? and (2) Are patients seeing one particular physician?” Dr. Traina explained. “One important key takeaway is the importance of frequently communicating simple messages through multiple mechanisms, including signage, websites, and dedicated resources.”

Other key technological measures are leveraging telemedicine to convert inpatient appointments to a virtual setting, as well as developing and deploying a system for centralized outpatient follow-up of COVID-19-positive patients.

“We saw a 3,000% increase in telemedicine utilization from February 2020 to June 2020,” Dr. Traina reported. “In a given month, we have approximately 230,000 outpatient visits, and a substantial proportion of these are now done via telemedicine.”

Dr. Traina also noted that multiple organizations have released guidelines addressing when to resume anticancer therapy in patients who have been COVID-19 positive. Adherence is important, as unnecessary COVID-19 testing may delay cancer therapy and is not recommended.

During a live discussion, Louis P. Voigt, MD, of MSKCC, said Dr. Traina’s presentation provided “a lot of good ideas for other institutions who may be facing similar challenges.”

Dr. Traina and Dr. Voigt disclosed no conflicts of interest. No funding sources were reported.

Best practices for managing cancer outpatients continue to evolve during the COVID-19 pandemic, with recent innovations in technology, operations, and communication.

“We’ve tried a lot of new things to ensure optimal care for our patients,” said Tiffany A. Traina, MD, of Memorial Sloan Kettering Cancer Center (MSKCC) in New York. “We need to effectively utilize all resources at our disposal to keep in touch with our patients during this time.”

Dr. Traina described the approach to outpatient management used at MSKCC during a presentation at the AACR Virtual Meeting: COVID-19 and Cancer.
 

Four guiding principles

MSKCC has established four guiding principles on how to manage cancer patients during the pandemic: openness, safety, technology, and staffing.

Openness ensures that decisions are guided by clinical priorities to provide optimal patient care and allow for prioritization of clinical research and education, Dr. Traina said.

The safety of patients and staff is of the utmost importance, she added. To ensure safety in the context of outpatient care, several operational levers were developed, including COVID surge planning, universal masking and personal protective equipment guidelines, remote work, clinical levers, and new dashboards and communications.

Dr. Traina said data analytics and dashboards have been key technological tools used to support evidence-based decision-making and deliver care remotely for patients during the pandemic.

Staffing resources have also shifted to support demand at different health system locations.
 

Screening, cohorting, and telemedicine

One measure MSKCC adopted is the MSK Engage Questionnaire, a COVID-19 screening questionnaire assigned to every patient with a scheduled outpatient visit. After completing the questionnaire, patients receive a response denoting whether they need to come into the outpatient setting.

On the staffing side, clinic coordinators prepare appointments accordingly, based on the risk level for each patient.

“We also try to cohort COVID-positive patients into particular areas within the outpatient setting,” Dr. Traina explained. “In addition, we control flow through ambulatory care locations by having separate patient entrances and use other tools to make flow as efficient as possible.”

On the technology side, interactive dashboards are being used to model traffic through different buildings.

“These data and analytics are useful for operational engineering, answering questions such as (1) Are there backups in chemotherapy? and (2) Are patients seeing one particular physician?” Dr. Traina explained. “One important key takeaway is the importance of frequently communicating simple messages through multiple mechanisms, including signage, websites, and dedicated resources.”

Other key technological measures are leveraging telemedicine to convert inpatient appointments to a virtual setting, as well as developing and deploying a system for centralized outpatient follow-up of COVID-19-positive patients.

“We saw a 3,000% increase in telemedicine utilization from February 2020 to June 2020,” Dr. Traina reported. “In a given month, we have approximately 230,000 outpatient visits, and a substantial proportion of these are now done via telemedicine.”

Dr. Traina also noted that multiple organizations have released guidelines addressing when to resume anticancer therapy in patients who have been COVID-19 positive. Adherence is important, as unnecessary COVID-19 testing may delay cancer therapy and is not recommended.

During a live discussion, Louis P. Voigt, MD, of MSKCC, said Dr. Traina’s presentation provided “a lot of good ideas for other institutions who may be facing similar challenges.”

Dr. Traina and Dr. Voigt disclosed no conflicts of interest. No funding sources were reported.

Best practices for managing cancer outpatients continue to evolve during the COVID-19 pandemic, with recent innovations in technology, operations, and communication.

“We’ve tried a lot of new things to ensure optimal care for our patients,” said Tiffany A. Traina, MD, of Memorial Sloan Kettering Cancer Center (MSKCC) in New York. “We need to effectively utilize all resources at our disposal to keep in touch with our patients during this time.”

Dr. Traina described the approach to outpatient management used at MSKCC during a presentation at the AACR Virtual Meeting: COVID-19 and Cancer.
 

Four guiding principles

MSKCC has established four guiding principles on how to manage cancer patients during the pandemic: openness, safety, technology, and staffing.

Openness ensures that decisions are guided by clinical priorities to provide optimal patient care and allow for prioritization of clinical research and education, Dr. Traina said.

The safety of patients and staff is of the utmost importance, she added. To ensure safety in the context of outpatient care, several operational levers were developed, including COVID surge planning, universal masking and personal protective equipment guidelines, remote work, clinical levers, and new dashboards and communications.

Dr. Traina said data analytics and dashboards have been key technological tools used to support evidence-based decision-making and deliver care remotely for patients during the pandemic.

Staffing resources have also shifted to support demand at different health system locations.
 

Screening, cohorting, and telemedicine

One measure MSKCC adopted is the MSK Engage Questionnaire, a COVID-19 screening questionnaire assigned to every patient with a scheduled outpatient visit. After completing the questionnaire, patients receive a response denoting whether they need to come into the outpatient setting.

On the staffing side, clinic coordinators prepare appointments accordingly, based on the risk level for each patient.

“We also try to cohort COVID-positive patients into particular areas within the outpatient setting,” Dr. Traina explained. “In addition, we control flow through ambulatory care locations by having separate patient entrances and use other tools to make flow as efficient as possible.”

On the technology side, interactive dashboards are being used to model traffic through different buildings.

“These data and analytics are useful for operational engineering, answering questions such as (1) Are there backups in chemotherapy? and (2) Are patients seeing one particular physician?” Dr. Traina explained. “One important key takeaway is the importance of frequently communicating simple messages through multiple mechanisms, including signage, websites, and dedicated resources.”

Other key technological measures are leveraging telemedicine to convert inpatient appointments to a virtual setting, as well as developing and deploying a system for centralized outpatient follow-up of COVID-19-positive patients.

“We saw a 3,000% increase in telemedicine utilization from February 2020 to June 2020,” Dr. Traina reported. “In a given month, we have approximately 230,000 outpatient visits, and a substantial proportion of these are now done via telemedicine.”

Dr. Traina also noted that multiple organizations have released guidelines addressing when to resume anticancer therapy in patients who have been COVID-19 positive. Adherence is important, as unnecessary COVID-19 testing may delay cancer therapy and is not recommended.

During a live discussion, Louis P. Voigt, MD, of MSKCC, said Dr. Traina’s presentation provided “a lot of good ideas for other institutions who may be facing similar challenges.”

Dr. Traina and Dr. Voigt disclosed no conflicts of interest. No funding sources were reported.

In women, breast cancer is the leading cancer diagnosis and the second leading cause of cancer-related death,¹ as well as the most common malignancy to metastasize to the skin.² Cutaneous breast carcinoma may present as cutaneous metastasis or can occur secondary to direct tumor extension. Five percent to 10% of women with breast cancer will present clinically with metastatic cutaneous disease, most commonly as a recurrence of early-stage breast carcinoma.²

In a published meta-analysis that investigated the incidence of tumors most commonly found to metastasize to the skin, Krathen et al³ found that cutaneous metastases occurred in 24% of patients with breast cancer (N=1903). In 2 large retrospective studies from tumor registry data, breast cancer was found to be the most common tumor involving metastasis to the skin, and 3.5% of the breast cancer cases identified in the registry had cutaneous metastasis as the presenting sign (n=35) at time of diagnosis.⁴

We report an unusual presentation of cutaneous metastatic lobular breast carcinoma that involved diffuse cutaneous lesions and rapid progression from onset of the breast mass to development of clinically apparent metastatic skin lesions.

Case Report

A 59-year-old woman with an unremarkable medical history presented to our dermatology clinic for evaluation of new widespread lesions that developed over a period of months. The eruption was asymptomatic and consisted of numerous bumpy lesions that reportedly started on the patient’s neck and progressively spread to involve the trunk. Physical examination revealed multiple flesh-colored, firm nodules scattered across the upper back, neck, and chest (Figure 1). Bilateral cervical and axillary lymphadenopathy also was noted. Upon questioning regarding family history of malignancy, the patient reported that her brother had been diagnosed with colon cancer. Although she was not up to date on age-appropriate malignancy screenings, she did report having a diagnostic mammogram 1 year prior that revealed a suspicious lesion on the left breast. A repeat mammogram of the left breast 6 months later was read as unremarkable.

Two 3-mm representative punch biopsies were performed. Hematoxylin and eosin staining revealed a basket-weave stratum corneum with underlying epidermal atrophy. A relatively monomorphic epithelioid cell infiltrate extending from the superficial reticular dermis into the deep dermis and displaying an open chromatin pattern and pink cytoplasm was observed, as well as dermal collagen thickening. Linear, single-filing cells along with focal irregular nests and scattered cells were observed (Figure 2). Immunohistochemical staining was positive for cytokeratin 7 (Figure 3A), epithelial membrane antigen, and estrogen receptor (Figure 3B) along with gross cystic disease fluid protein 15; focal progesterone receptor positivity also was present. Cytokeratin 20, cytokeratin 5/6, carcinoembryonic antigen, p63, CDX2, paired box gene 8, thyroid transcription factor 1, and human epidermal growth factor receptor 2/neu stains were negative. Findings identified in both biopsies were consistent with metastatic cutaneous lobular breast carcinoma.

A complete blood cell count and complete metabolic panels were within normal limits, aside from a mildly elevated alkaline phosphatase level. Breast ultrasonography was unremarkable. Stereotactic breast magnetic resonance imaging (MRI) revealed a 9.4-cm mass in the upper outer quadrant of the right breast as well as enlarged lymph nodes 2.2 cm from the left axilla. A subsequent bone scan demonstrated focal activity in the left lateral fourth rib, left costochondral junction, and right anterolateral fifth rib—it was unclear whether these lesions were metastatic or secondary to trauma from a fall the patient reportedly had sustained 2 weeks prior. Lumbar MRI without gadolinium contrast revealed extensive abnormal heterogeneous signal intensity of osseous structures consistent with osseous metastasis.

Subsequent diagnostic bilateral breast ultrasonography and percutaneous left lymph node biopsy revealed pathology consistent with metastatic lobular breast carcinoma with near total effacement of the lymph node and extracapsular extension concordant with previous MRI findings. The mass in the upper outer quadrant of the right breast that previously was observed on MRI was not identifiable on this ultrasound. It was recommended that the patient pursue MRI-guided breast biopsy to have the breast lesion further characterized. She was referred to surgical oncology at a tertiary center for management; however, the patient was lost to follow-up, and there are no records available indicating the patient pursued any treatment. Although we were unable to confirm the patient’s breast lesion that previously was seen on MRI was the cause of the metastatic disease, the overall clinical picture supported metastatic lobular breast carcinoma.

Comment

Tumor metastasis to the skin accounts for approximately 2% of all skin cancers⁵ and typically is observed in advanced stages of cancer. In women, breast carcinoma is the most common type of cancer to exhibit this behavior.² Invasive ductal carcinoma represents the most common histologic subtype of breast cancer overall,^6,7 and breast adenocarcinomas, including lobular and ductal breast carcinomas, are the most common histologic subtypes to exhibit metastatic cutaneous lesions.⁸

Invasive lobular breast carcinoma represents approximately 10% of invasive breast cancer cases. Compared to invasive ductal carcinoma, there tends to be a delay in diagnosis often leading to larger tumor sizes relative to the former upon detection and with lymph node invasion. These findings may be explained by the greater difficulty of detecting invasive lobular carcinomas by mammography and clinical breast examination compared to invasive ductal carcinomas.^9-11 Additionally, invasive lobular carcinomas are more likely to be positive for estrogen and progesterone receptors compared to invasive ductal carcinomas,¹² which also was consistent in our case.

Cutaneous metastases of breast cancer most commonly are found on the anterior chest wall and can present as a wide spectrum of lesions, with nodules as the most common primary dermatologic manifestation.¹³ Cutaneous metastatic lesions commonly have been described as firm, mobile, round or oval, solitary or grouped nodules. The color of the nodules varies and may be flesh-colored, brown, blue, black, pink, and/or red-brown. The lesions often are asymptomatic but may ulcerate.²

In our case, the distribution of lesions was a unique aspect that is not typical of most cases of metastatic cutaneous breast carcinoma. The nodules appeared more scattered and involved multiple body regions, including the back, neck, and chest. Although cutaneous breast cancer metastases have been documented to extend to these body regions, a review of PubMed articles indexed for MEDLINE using the terms cutaneous metastatic lobular breast carcinoma, breast carcinoma, and metastatic breast cancer suggested that it is uncommon for these multiple areas to be simultaneously affected.^4,14 Rather, the more common clinical presentation of cutaneous metastatic breast carcinoma is as a solitary nodule or group of nodules localized to a single anatomic region.¹⁴

Another notable feature of our case was the rapid development of the cutaneous lesions relative to the primary tumor. This patient developed diffuse lesions over a period of several months, and given that her mammogram performed the previous year was negative for any abnormalities, one could suggest that the metastatic lesions developed less than a year from onset of the primary tumor. A previous study involving 41 patients with a known clinical primary visceral malignancy (ie, breast, lung, colon, esophageal, gastric, pancreatic, kidney, thyroid, prostate, or ovarian origin) found that it takes approximately 3 years on average for cutaneous metastases to develop from the onset of cancer diagnosis (range, 1–177 months).¹⁴ In the aforementioned study, 94% of patients had stage III or IV disease at time of skin metastasis, with the majority of those demonstrating stage IV disease. However, it also is possible that these breast tumors evaded detection or were too small to be identified on prior imaging.¹⁴ A review of our patient’s medical records did not indicate documentation of any visual or palpable breast changes prior to the onset of the clinically detected metastatic nodules.

Conclusion

Biopsy with immunohistochemical staining ultimately yielded the diagnosis of metastatic lobular breast carcinoma in our patient. Providers should be aware of the varying clinical presentations that may arise in the setting of cutaneous metastasis. When faced with lesions suspicious for cutaneous metastasis, biopsy is warranted to determine the correct diagnosis and ensure appropriate management. Upon diagnosis of cutaneous metastasis, prompt coordination with the primary care provider and appropriate referral to multidisciplinary teams is necessary. Clinical providers also should maintain a high index of suspicion when evaluating patients with cutaneous metastasis who have a history of normal malignancy screenings.

In women, breast cancer is the leading cancer diagnosis and the second leading cause of cancer-related death,¹ as well as the most common malignancy to metastasize to the skin.² Cutaneous breast carcinoma may present as cutaneous metastasis or can occur secondary to direct tumor extension. Five percent to 10% of women with breast cancer will present clinically with metastatic cutaneous disease, most commonly as a recurrence of early-stage breast carcinoma.²

In a published meta-analysis that investigated the incidence of tumors most commonly found to metastasize to the skin, Krathen et al³ found that cutaneous metastases occurred in 24% of patients with breast cancer (N=1903). In 2 large retrospective studies from tumor registry data, breast cancer was found to be the most common tumor involving metastasis to the skin, and 3.5% of the breast cancer cases identified in the registry had cutaneous metastasis as the presenting sign (n=35) at time of diagnosis.⁴

We report an unusual presentation of cutaneous metastatic lobular breast carcinoma that involved diffuse cutaneous lesions and rapid progression from onset of the breast mass to development of clinically apparent metastatic skin lesions.

Case Report

A 59-year-old woman with an unremarkable medical history presented to our dermatology clinic for evaluation of new widespread lesions that developed over a period of months. The eruption was asymptomatic and consisted of numerous bumpy lesions that reportedly started on the patient’s neck and progressively spread to involve the trunk. Physical examination revealed multiple flesh-colored, firm nodules scattered across the upper back, neck, and chest (Figure 1). Bilateral cervical and axillary lymphadenopathy also was noted. Upon questioning regarding family history of malignancy, the patient reported that her brother had been diagnosed with colon cancer. Although she was not up to date on age-appropriate malignancy screenings, she did report having a diagnostic mammogram 1 year prior that revealed a suspicious lesion on the left breast. A repeat mammogram of the left breast 6 months later was read as unremarkable.

Two 3-mm representative punch biopsies were performed. Hematoxylin and eosin staining revealed a basket-weave stratum corneum with underlying epidermal atrophy. A relatively monomorphic epithelioid cell infiltrate extending from the superficial reticular dermis into the deep dermis and displaying an open chromatin pattern and pink cytoplasm was observed, as well as dermal collagen thickening. Linear, single-filing cells along with focal irregular nests and scattered cells were observed (Figure 2). Immunohistochemical staining was positive for cytokeratin 7 (Figure 3A), epithelial membrane antigen, and estrogen receptor (Figure 3B) along with gross cystic disease fluid protein 15; focal progesterone receptor positivity also was present. Cytokeratin 20, cytokeratin 5/6, carcinoembryonic antigen, p63, CDX2, paired box gene 8, thyroid transcription factor 1, and human epidermal growth factor receptor 2/neu stains were negative. Findings identified in both biopsies were consistent with metastatic cutaneous lobular breast carcinoma.

A complete blood cell count and complete metabolic panels were within normal limits, aside from a mildly elevated alkaline phosphatase level. Breast ultrasonography was unremarkable. Stereotactic breast magnetic resonance imaging (MRI) revealed a 9.4-cm mass in the upper outer quadrant of the right breast as well as enlarged lymph nodes 2.2 cm from the left axilla. A subsequent bone scan demonstrated focal activity in the left lateral fourth rib, left costochondral junction, and right anterolateral fifth rib—it was unclear whether these lesions were metastatic or secondary to trauma from a fall the patient reportedly had sustained 2 weeks prior. Lumbar MRI without gadolinium contrast revealed extensive abnormal heterogeneous signal intensity of osseous structures consistent with osseous metastasis.

Subsequent diagnostic bilateral breast ultrasonography and percutaneous left lymph node biopsy revealed pathology consistent with metastatic lobular breast carcinoma with near total effacement of the lymph node and extracapsular extension concordant with previous MRI findings. The mass in the upper outer quadrant of the right breast that previously was observed on MRI was not identifiable on this ultrasound. It was recommended that the patient pursue MRI-guided breast biopsy to have the breast lesion further characterized. She was referred to surgical oncology at a tertiary center for management; however, the patient was lost to follow-up, and there are no records available indicating the patient pursued any treatment. Although we were unable to confirm the patient’s breast lesion that previously was seen on MRI was the cause of the metastatic disease, the overall clinical picture supported metastatic lobular breast carcinoma.

Comment

Tumor metastasis to the skin accounts for approximately 2% of all skin cancers⁵ and typically is observed in advanced stages of cancer. In women, breast carcinoma is the most common type of cancer to exhibit this behavior.² Invasive ductal carcinoma represents the most common histologic subtype of breast cancer overall,^6,7 and breast adenocarcinomas, including lobular and ductal breast carcinomas, are the most common histologic subtypes to exhibit metastatic cutaneous lesions.⁸

Invasive lobular breast carcinoma represents approximately 10% of invasive breast cancer cases. Compared to invasive ductal carcinoma, there tends to be a delay in diagnosis often leading to larger tumor sizes relative to the former upon detection and with lymph node invasion. These findings may be explained by the greater difficulty of detecting invasive lobular carcinomas by mammography and clinical breast examination compared to invasive ductal carcinomas.^9-11 Additionally, invasive lobular carcinomas are more likely to be positive for estrogen and progesterone receptors compared to invasive ductal carcinomas,¹² which also was consistent in our case.

Cutaneous metastases of breast cancer most commonly are found on the anterior chest wall and can present as a wide spectrum of lesions, with nodules as the most common primary dermatologic manifestation.¹³ Cutaneous metastatic lesions commonly have been described as firm, mobile, round or oval, solitary or grouped nodules. The color of the nodules varies and may be flesh-colored, brown, blue, black, pink, and/or red-brown. The lesions often are asymptomatic but may ulcerate.²

In our case, the distribution of lesions was a unique aspect that is not typical of most cases of metastatic cutaneous breast carcinoma. The nodules appeared more scattered and involved multiple body regions, including the back, neck, and chest. Although cutaneous breast cancer metastases have been documented to extend to these body regions, a review of PubMed articles indexed for MEDLINE using the terms cutaneous metastatic lobular breast carcinoma, breast carcinoma, and metastatic breast cancer suggested that it is uncommon for these multiple areas to be simultaneously affected.^4,14 Rather, the more common clinical presentation of cutaneous metastatic breast carcinoma is as a solitary nodule or group of nodules localized to a single anatomic region.¹⁴

Another notable feature of our case was the rapid development of the cutaneous lesions relative to the primary tumor. This patient developed diffuse lesions over a period of several months, and given that her mammogram performed the previous year was negative for any abnormalities, one could suggest that the metastatic lesions developed less than a year from onset of the primary tumor. A previous study involving 41 patients with a known clinical primary visceral malignancy (ie, breast, lung, colon, esophageal, gastric, pancreatic, kidney, thyroid, prostate, or ovarian origin) found that it takes approximately 3 years on average for cutaneous metastases to develop from the onset of cancer diagnosis (range, 1–177 months).¹⁴ In the aforementioned study, 94% of patients had stage III or IV disease at time of skin metastasis, with the majority of those demonstrating stage IV disease. However, it also is possible that these breast tumors evaded detection or were too small to be identified on prior imaging.¹⁴ A review of our patient’s medical records did not indicate documentation of any visual or palpable breast changes prior to the onset of the clinically detected metastatic nodules.

Conclusion

Biopsy with immunohistochemical staining ultimately yielded the diagnosis of metastatic lobular breast carcinoma in our patient. Providers should be aware of the varying clinical presentations that may arise in the setting of cutaneous metastasis. When faced with lesions suspicious for cutaneous metastasis, biopsy is warranted to determine the correct diagnosis and ensure appropriate management. Upon diagnosis of cutaneous metastasis, prompt coordination with the primary care provider and appropriate referral to multidisciplinary teams is necessary. Clinical providers also should maintain a high index of suspicion when evaluating patients with cutaneous metastasis who have a history of normal malignancy screenings.

In women, breast cancer is the leading cancer diagnosis and the second leading cause of cancer-related death,¹ as well as the most common malignancy to metastasize to the skin.² Cutaneous breast carcinoma may present as cutaneous metastasis or can occur secondary to direct tumor extension. Five percent to 10% of women with breast cancer will present clinically with metastatic cutaneous disease, most commonly as a recurrence of early-stage breast carcinoma.²

In a published meta-analysis that investigated the incidence of tumors most commonly found to metastasize to the skin, Krathen et al³ found that cutaneous metastases occurred in 24% of patients with breast cancer (N=1903). In 2 large retrospective studies from tumor registry data, breast cancer was found to be the most common tumor involving metastasis to the skin, and 3.5% of the breast cancer cases identified in the registry had cutaneous metastasis as the presenting sign (n=35) at time of diagnosis.⁴

We report an unusual presentation of cutaneous metastatic lobular breast carcinoma that involved diffuse cutaneous lesions and rapid progression from onset of the breast mass to development of clinically apparent metastatic skin lesions.

Case Report

A 59-year-old woman with an unremarkable medical history presented to our dermatology clinic for evaluation of new widespread lesions that developed over a period of months. The eruption was asymptomatic and consisted of numerous bumpy lesions that reportedly started on the patient’s neck and progressively spread to involve the trunk. Physical examination revealed multiple flesh-colored, firm nodules scattered across the upper back, neck, and chest (Figure 1). Bilateral cervical and axillary lymphadenopathy also was noted. Upon questioning regarding family history of malignancy, the patient reported that her brother had been diagnosed with colon cancer. Although she was not up to date on age-appropriate malignancy screenings, she did report having a diagnostic mammogram 1 year prior that revealed a suspicious lesion on the left breast. A repeat mammogram of the left breast 6 months later was read as unremarkable.

Two 3-mm representative punch biopsies were performed. Hematoxylin and eosin staining revealed a basket-weave stratum corneum with underlying epidermal atrophy. A relatively monomorphic epithelioid cell infiltrate extending from the superficial reticular dermis into the deep dermis and displaying an open chromatin pattern and pink cytoplasm was observed, as well as dermal collagen thickening. Linear, single-filing cells along with focal irregular nests and scattered cells were observed (Figure 2). Immunohistochemical staining was positive for cytokeratin 7 (Figure 3A), epithelial membrane antigen, and estrogen receptor (Figure 3B) along with gross cystic disease fluid protein 15; focal progesterone receptor positivity also was present. Cytokeratin 20, cytokeratin 5/6, carcinoembryonic antigen, p63, CDX2, paired box gene 8, thyroid transcription factor 1, and human epidermal growth factor receptor 2/neu stains were negative. Findings identified in both biopsies were consistent with metastatic cutaneous lobular breast carcinoma.

A complete blood cell count and complete metabolic panels were within normal limits, aside from a mildly elevated alkaline phosphatase level. Breast ultrasonography was unremarkable. Stereotactic breast magnetic resonance imaging (MRI) revealed a 9.4-cm mass in the upper outer quadrant of the right breast as well as enlarged lymph nodes 2.2 cm from the left axilla. A subsequent bone scan demonstrated focal activity in the left lateral fourth rib, left costochondral junction, and right anterolateral fifth rib—it was unclear whether these lesions were metastatic or secondary to trauma from a fall the patient reportedly had sustained 2 weeks prior. Lumbar MRI without gadolinium contrast revealed extensive abnormal heterogeneous signal intensity of osseous structures consistent with osseous metastasis.

Subsequent diagnostic bilateral breast ultrasonography and percutaneous left lymph node biopsy revealed pathology consistent with metastatic lobular breast carcinoma with near total effacement of the lymph node and extracapsular extension concordant with previous MRI findings. The mass in the upper outer quadrant of the right breast that previously was observed on MRI was not identifiable on this ultrasound. It was recommended that the patient pursue MRI-guided breast biopsy to have the breast lesion further characterized. She was referred to surgical oncology at a tertiary center for management; however, the patient was lost to follow-up, and there are no records available indicating the patient pursued any treatment. Although we were unable to confirm the patient’s breast lesion that previously was seen on MRI was the cause of the metastatic disease, the overall clinical picture supported metastatic lobular breast carcinoma.

Comment

Tumor metastasis to the skin accounts for approximately 2% of all skin cancers⁵ and typically is observed in advanced stages of cancer. In women, breast carcinoma is the most common type of cancer to exhibit this behavior.² Invasive ductal carcinoma represents the most common histologic subtype of breast cancer overall,^6,7 and breast adenocarcinomas, including lobular and ductal breast carcinomas, are the most common histologic subtypes to exhibit metastatic cutaneous lesions.⁸

Invasive lobular breast carcinoma represents approximately 10% of invasive breast cancer cases. Compared to invasive ductal carcinoma, there tends to be a delay in diagnosis often leading to larger tumor sizes relative to the former upon detection and with lymph node invasion. These findings may be explained by the greater difficulty of detecting invasive lobular carcinomas by mammography and clinical breast examination compared to invasive ductal carcinomas.^9-11 Additionally, invasive lobular carcinomas are more likely to be positive for estrogen and progesterone receptors compared to invasive ductal carcinomas,¹² which also was consistent in our case.

Cutaneous metastases of breast cancer most commonly are found on the anterior chest wall and can present as a wide spectrum of lesions, with nodules as the most common primary dermatologic manifestation.¹³ Cutaneous metastatic lesions commonly have been described as firm, mobile, round or oval, solitary or grouped nodules. The color of the nodules varies and may be flesh-colored, brown, blue, black, pink, and/or red-brown. The lesions often are asymptomatic but may ulcerate.²

In our case, the distribution of lesions was a unique aspect that is not typical of most cases of metastatic cutaneous breast carcinoma. The nodules appeared more scattered and involved multiple body regions, including the back, neck, and chest. Although cutaneous breast cancer metastases have been documented to extend to these body regions, a review of PubMed articles indexed for MEDLINE using the terms cutaneous metastatic lobular breast carcinoma, breast carcinoma, and metastatic breast cancer suggested that it is uncommon for these multiple areas to be simultaneously affected.^4,14 Rather, the more common clinical presentation of cutaneous metastatic breast carcinoma is as a solitary nodule or group of nodules localized to a single anatomic region.¹⁴

Another notable feature of our case was the rapid development of the cutaneous lesions relative to the primary tumor. This patient developed diffuse lesions over a period of several months, and given that her mammogram performed the previous year was negative for any abnormalities, one could suggest that the metastatic lesions developed less than a year from onset of the primary tumor. A previous study involving 41 patients with a known clinical primary visceral malignancy (ie, breast, lung, colon, esophageal, gastric, pancreatic, kidney, thyroid, prostate, or ovarian origin) found that it takes approximately 3 years on average for cutaneous metastases to develop from the onset of cancer diagnosis (range, 1–177 months).¹⁴ In the aforementioned study, 94% of patients had stage III or IV disease at time of skin metastasis, with the majority of those demonstrating stage IV disease. However, it also is possible that these breast tumors evaded detection or were too small to be identified on prior imaging.¹⁴ A review of our patient’s medical records did not indicate documentation of any visual or palpable breast changes prior to the onset of the clinically detected metastatic nodules.

Conclusion

Biopsy with immunohistochemical staining ultimately yielded the diagnosis of metastatic lobular breast carcinoma in our patient. Providers should be aware of the varying clinical presentations that may arise in the setting of cutaneous metastasis. When faced with lesions suspicious for cutaneous metastasis, biopsy is warranted to determine the correct diagnosis and ensure appropriate management. Upon diagnosis of cutaneous metastasis, prompt coordination with the primary care provider and appropriate referral to multidisciplinary teams is necessary. Clinical providers also should maintain a high index of suspicion when evaluating patients with cutaneous metastasis who have a history of normal malignancy screenings.

The Diagnosis: Bazex‐Dupré‐Christol Syndrome

Bazex‐Dupré‐Christol syndrome (BDCS) is a rare X-linked dominant genodermatosis characterized by a triad of hypotrichosis, follicular atrophoderma, and multiple basal cell carcinomas (BCCs). Since first being described in 1964,¹ there have been fewer than 200 reported cases of BDCS.² Although a causative gene has not yet been identified, the mutation has been mapped to an 11.4-Mb interval in the Xq25-27.1 region of the X chromosome.³

Classically, congenital hypotrichosis is the first observed symptom and can present shortly after birth.⁴ It typically is widespread, though sometimes it may be confined to the eyebrows, eyelashes, and scalp. Follicular atrophoderma, which occurs due to a laxation and deepening of the follicular ostia, is seen in 80% of cases and typically presents in early childhood as depressions lacking hair.² It commonly is found on the face, extensor surfaces of the elbows and knees, and dorsal aspects of the hands and feet. Physical examination of our patient revealed follicular atrophoderma on both the dorsal surfaces of the hands and the extensor surfaces of the elbows. Hair shaft anomalies including pili torti, pili bifurcati, and trichorrhexis nodosa are infrequently observed symptoms of BDCS.²

Basal cell carcinoma often manifests in the second or third decades of life, though there are reports of BCC developing in BDCS patients as young as 3 years. Basal cell carcinoma typically arises on sun-exposed areas, especially the face, neck, and chest. These lesions can be pigmented or nonpigmented and range from 2 to 20 mm in diameter.⁴ Our patient presented with a BCC on the forehead (Figure 1). Histopathologic evaluation showed a proliferation of basaloid cells with peripheral palisading (Figure 2), confirming the diagnosis of BCC.

Milia, which are not considered part of the classic BDCS triad, are seen in 70% of cases.² They commonly are found on the face and often diminish with age. Milia may precede the formation of follicular atrophoderma and BCC. Hypohidrosis most commonly occurs on the forehead but can be widespread.² Other less commonly observed features include epidermal cysts, hyperpigmentation of the face, and trichoepitheliomas.⁴ The management of BDCS involves frequent clinical examinations, BCC treatment, genetic counseling, and photoprotection.^2,4

Nevoid BCC syndrome (NBCCS), also known as Gorlin-Goltz syndrome, is an autosomal-dominant disease characterized by multiple nevoid BCCs, macrocephaly with a large forehead, cleft lip or palate, jaw keratocysts, palmar and plantar pits, and calcification of the falx cerebri.⁵ Nevoid BCC syndrome is caused by a mutation in the PTCH1 gene in the hedgehog signaling pathway.⁶ The absence of common symptoms of NBCCS including macrocephaly, palmar or plantar pits, and cleft lip or palate, as well as negative genetic testing, suggested that our patient did not have NBCCS.

Rombo syndrome shares features with BDCS. Similar to BDCS, symptoms of Rombo syndrome include follicular atrophy, milialike papules, and BCC. Patients with Rombo syndrome typically present with atrophoderma vermiculatum on the cheeks and forehead in childhood.⁷ This atrophoderma presents with a pitted atrophic appearance in a reticular pattern on sun-exposed areas. Other distinguishing features from BDCS include cyanotic redness of sun-exposed skin and telangiectatic vessels.⁸

Multiple hereditary infundibulocystic BCC is another rare genodermatosis that is characterized by the presence of multiple infundibulocystic BCCs on the face and genitals. Infundibulocystic BCC is a well-differentiated subtype of BCC characterized by buds and cords of basaloid cells with scant stroma. Multiple hereditary infundibulocystic BCC is inherited in an autosomal-dominant fashion and has been linked to ^SUFU mutation in the sonic hedgehog pathway.⁹

Rothmund-Thomson syndrome is an autosomalrecessive disorder characterized by sparse hair, skeletal and dental abnormalities, and a high risk for developing keratinocyte carcinomas. It is differentiated from BDCS clinically by the presence of erythema, edema, and blistering, resulting in poikiloderma, plantar hyperkeratotic lesions, and bone defects.¹⁰

The Diagnosis: Bazex‐Dupré‐Christol Syndrome

Bazex‐Dupré‐Christol syndrome (BDCS) is a rare X-linked dominant genodermatosis characterized by a triad of hypotrichosis, follicular atrophoderma, and multiple basal cell carcinomas (BCCs). Since first being described in 1964,¹ there have been fewer than 200 reported cases of BDCS.² Although a causative gene has not yet been identified, the mutation has been mapped to an 11.4-Mb interval in the Xq25-27.1 region of the X chromosome.³

Classically, congenital hypotrichosis is the first observed symptom and can present shortly after birth.⁴ It typically is widespread, though sometimes it may be confined to the eyebrows, eyelashes, and scalp. Follicular atrophoderma, which occurs due to a laxation and deepening of the follicular ostia, is seen in 80% of cases and typically presents in early childhood as depressions lacking hair.² It commonly is found on the face, extensor surfaces of the elbows and knees, and dorsal aspects of the hands and feet. Physical examination of our patient revealed follicular atrophoderma on both the dorsal surfaces of the hands and the extensor surfaces of the elbows. Hair shaft anomalies including pili torti, pili bifurcati, and trichorrhexis nodosa are infrequently observed symptoms of BDCS.²

Basal cell carcinoma often manifests in the second or third decades of life, though there are reports of BCC developing in BDCS patients as young as 3 years. Basal cell carcinoma typically arises on sun-exposed areas, especially the face, neck, and chest. These lesions can be pigmented or nonpigmented and range from 2 to 20 mm in diameter.⁴ Our patient presented with a BCC on the forehead (Figure 1). Histopathologic evaluation showed a proliferation of basaloid cells with peripheral palisading (Figure 2), confirming the diagnosis of BCC.

Milia, which are not considered part of the classic BDCS triad, are seen in 70% of cases.² They commonly are found on the face and often diminish with age. Milia may precede the formation of follicular atrophoderma and BCC. Hypohidrosis most commonly occurs on the forehead but can be widespread.² Other less commonly observed features include epidermal cysts, hyperpigmentation of the face, and trichoepitheliomas.⁴ The management of BDCS involves frequent clinical examinations, BCC treatment, genetic counseling, and photoprotection.^2,4

Nevoid BCC syndrome (NBCCS), also known as Gorlin-Goltz syndrome, is an autosomal-dominant disease characterized by multiple nevoid BCCs, macrocephaly with a large forehead, cleft lip or palate, jaw keratocysts, palmar and plantar pits, and calcification of the falx cerebri.⁵ Nevoid BCC syndrome is caused by a mutation in the PTCH1 gene in the hedgehog signaling pathway.⁶ The absence of common symptoms of NBCCS including macrocephaly, palmar or plantar pits, and cleft lip or palate, as well as negative genetic testing, suggested that our patient did not have NBCCS.

Rombo syndrome shares features with BDCS. Similar to BDCS, symptoms of Rombo syndrome include follicular atrophy, milialike papules, and BCC. Patients with Rombo syndrome typically present with atrophoderma vermiculatum on the cheeks and forehead in childhood.⁷ This atrophoderma presents with a pitted atrophic appearance in a reticular pattern on sun-exposed areas. Other distinguishing features from BDCS include cyanotic redness of sun-exposed skin and telangiectatic vessels.⁸

Multiple hereditary infundibulocystic BCC is another rare genodermatosis that is characterized by the presence of multiple infundibulocystic BCCs on the face and genitals. Infundibulocystic BCC is a well-differentiated subtype of BCC characterized by buds and cords of basaloid cells with scant stroma. Multiple hereditary infundibulocystic BCC is inherited in an autosomal-dominant fashion and has been linked to ^SUFU mutation in the sonic hedgehog pathway.⁹

Rothmund-Thomson syndrome is an autosomalrecessive disorder characterized by sparse hair, skeletal and dental abnormalities, and a high risk for developing keratinocyte carcinomas. It is differentiated from BDCS clinically by the presence of erythema, edema, and blistering, resulting in poikiloderma, plantar hyperkeratotic lesions, and bone defects.¹⁰

The Diagnosis: Bazex‐Dupré‐Christol Syndrome

Bazex‐Dupré‐Christol syndrome (BDCS) is a rare X-linked dominant genodermatosis characterized by a triad of hypotrichosis, follicular atrophoderma, and multiple basal cell carcinomas (BCCs). Since first being described in 1964,¹ there have been fewer than 200 reported cases of BDCS.² Although a causative gene has not yet been identified, the mutation has been mapped to an 11.4-Mb interval in the Xq25-27.1 region of the X chromosome.³

Classically, congenital hypotrichosis is the first observed symptom and can present shortly after birth.⁴ It typically is widespread, though sometimes it may be confined to the eyebrows, eyelashes, and scalp. Follicular atrophoderma, which occurs due to a laxation and deepening of the follicular ostia, is seen in 80% of cases and typically presents in early childhood as depressions lacking hair.² It commonly is found on the face, extensor surfaces of the elbows and knees, and dorsal aspects of the hands and feet. Physical examination of our patient revealed follicular atrophoderma on both the dorsal surfaces of the hands and the extensor surfaces of the elbows. Hair shaft anomalies including pili torti, pili bifurcati, and trichorrhexis nodosa are infrequently observed symptoms of BDCS.²

Basal cell carcinoma often manifests in the second or third decades of life, though there are reports of BCC developing in BDCS patients as young as 3 years. Basal cell carcinoma typically arises on sun-exposed areas, especially the face, neck, and chest. These lesions can be pigmented or nonpigmented and range from 2 to 20 mm in diameter.⁴ Our patient presented with a BCC on the forehead (Figure 1). Histopathologic evaluation showed a proliferation of basaloid cells with peripheral palisading (Figure 2), confirming the diagnosis of BCC.

Milia, which are not considered part of the classic BDCS triad, are seen in 70% of cases.² They commonly are found on the face and often diminish with age. Milia may precede the formation of follicular atrophoderma and BCC. Hypohidrosis most commonly occurs on the forehead but can be widespread.² Other less commonly observed features include epidermal cysts, hyperpigmentation of the face, and trichoepitheliomas.⁴ The management of BDCS involves frequent clinical examinations, BCC treatment, genetic counseling, and photoprotection.^2,4

Nevoid BCC syndrome (NBCCS), also known as Gorlin-Goltz syndrome, is an autosomal-dominant disease characterized by multiple nevoid BCCs, macrocephaly with a large forehead, cleft lip or palate, jaw keratocysts, palmar and plantar pits, and calcification of the falx cerebri.⁵ Nevoid BCC syndrome is caused by a mutation in the PTCH1 gene in the hedgehog signaling pathway.⁶ The absence of common symptoms of NBCCS including macrocephaly, palmar or plantar pits, and cleft lip or palate, as well as negative genetic testing, suggested that our patient did not have NBCCS.

Rombo syndrome shares features with BDCS. Similar to BDCS, symptoms of Rombo syndrome include follicular atrophy, milialike papules, and BCC. Patients with Rombo syndrome typically present with atrophoderma vermiculatum on the cheeks and forehead in childhood.⁷ This atrophoderma presents with a pitted atrophic appearance in a reticular pattern on sun-exposed areas. Other distinguishing features from BDCS include cyanotic redness of sun-exposed skin and telangiectatic vessels.⁸

Multiple hereditary infundibulocystic BCC is another rare genodermatosis that is characterized by the presence of multiple infundibulocystic BCCs on the face and genitals. Infundibulocystic BCC is a well-differentiated subtype of BCC characterized by buds and cords of basaloid cells with scant stroma. Multiple hereditary infundibulocystic BCC is inherited in an autosomal-dominant fashion and has been linked to ^SUFU mutation in the sonic hedgehog pathway.⁹

Rothmund-Thomson syndrome is an autosomalrecessive disorder characterized by sparse hair, skeletal and dental abnormalities, and a high risk for developing keratinocyte carcinomas. It is differentiated from BDCS clinically by the presence of erythema, edema, and blistering, resulting in poikiloderma, plantar hyperkeratotic lesions, and bone defects.¹⁰

All patients receiving active cancer treatment should receive a COVID-19 vaccine and should be prioritized for vaccination, according to preliminary recommendations from the National Comprehensive Cancer Network (NCCN).

Vaccination timing considerations vary based on factors such as cancer and treatment type, and reasons for delaying vaccination in the general public also apply to cancer patients (recent COVID-19 exposure, for example).

In general, however, patients with cancer should be assigned to Centers for Disease Control and Prevention priority group 1 b/c and immunized when vaccination is available to them, the guidelines state. Exceptions to this recommendation include:

• Patients undergoing hematopoietic stem cell transplant or receiving engineered cellular therapy such as chimeric antigen receptor T-cell therapy. Vaccination should be delayed for at least 3 months in these patients to maximize vaccine efficacy. Caregivers of these patients, however, should be immunized when possible.
• Patients with hematologic malignancies who are receiving intensive cytotoxic chemotherapy, such as cytarabine- or anthracycline-based regimens for acute myeloid leukemia. Vaccination in these patients should be delayed until absolute neutrophil count recovery.
• Patients undergoing major surgery. Vaccination should occur at least a few days before or after surgery.
• Patients who have experienced a severe or immediate adverse reaction to any of the ingredients in the mRNA COVID-19 vaccines.

Conversely, vaccination should occur when available in patients with hematologic malignancies and marrow failure who are expected to have limited or no recovery, patients with hematologic malignancies who are on long-term maintenance therapy, and patients with solid tumors who are receiving cytotoxic chemotherapy, targeted therapy, checkpoint inhibitors and other immunotherapy, or radiotherapy.

Caregivers, household contacts, and other close contacts who are 16 years of age and older should be vaccinated whenever they are eligible.
 

Unique concerns in patients with cancer

The NCCN recommendations were developed to address the unique issues and concerns with respect to patients with cancer, who have an increased risk of severe illness from SARS-CoV-2 infection. But the guidelines come with a caveat: “[t]here are limited safety and efficacy data in these patients,” the NCCN emphasized in a press statement.

“Right now, there is urgent need and limited data,” Steven Pergam, MD, co-leader of the NCCN COVID-19 Vaccination Committee, said in the statement.

“Our number one goal is helping to get the vaccine to as many people as we can,” Dr. Pergam said. “That means following existing national and regional directions for prioritizing people who are more likely to face death or severe illness from COVID-19.”

Dr. Pergam, associate professor at Fred Hutchinson Cancer Research Center in Seattle, further explained that “people receiving active cancer treatment are at greater risk for worse outcomes from COVID-19, particularly if they are older and have additional comorbidities, like immunosuppression.”

NCCN’s recommendations couldn’t have come at a better time for patients with cancer, according to Nora Disis, MD, a professor at the University of Washington in Seattle.

“The NCCN’s recommendations to prioritize COVID vaccinations for cancer patients on active treatment is an important step forward in protecting our patients from the infection,” Dr. Disis said in an interview.

“Cancer patients may be at higher risk for the complications seen with infection. In addition, cancer is a disease of older people, and a good number of our patients have the comorbidities that would predict a poorer outcome if they should become sick,” Dr. Disis added. “With the correct treatment, many patients with cancer will be long-term survivors. It is important that they be protected from infection with COVID to realize their best outcome.”
 

Additional vaccine considerations

The NCCN recommendations also address several other issues of importance for cancer patients, including:

• Deprioritizing other vaccines. COVID-19 vaccines should take precedence over other vaccines because data on dual vaccination are lacking. The NCCN recommends waiting 14 days after COVID-19 vaccination to deliver other vaccines.
• Vaccinating clinical trial participants. Trial leads should be consulted to prevent protocol violations or exclusions.
• Decision-making in the setting of limited vaccine availability. The NCCN noted that decisions on allocation must be made in accordance with state and local vaccine guidance but suggests prioritizing appropriate patients on active treatment, those planning to start treatment, and those who have just completed treatment. Additional risk factors for these patients, as well as other factors associated with risk for adverse COVID-19 outcomes, should also be considered. These include advanced age, comorbidities, and adverse social and demographic factors such as poverty and limited health care access.
• The need for ongoing prevention measures. Vaccines have been shown to decrease the incidence of COVID-19 and related complications, but it remains unclear whether vaccines prevent infection and subsequent transmission. This means everyone should continue following prevention recommendations, such as wearing masks and avoiding crowds.

The NCCN stressed that these recommendations are “intended to be a living document that is constantly evolving – it will be updated rapidly whenever new data comes out, as well as any potential new vaccines that may get approved in the future.” The NCCN also noted that the advisory committee will meet regularly to refine the recommendations as needed.

Dr. Pergam disclosed relationships with Chimerix Inc., Merck & Co., Global Life Technologies Inc., and Sanofi-Aventis. Dr. Disis disclosed grants from Pfizer, Bavarian Nordisk, Janssen, and Precigen. She is the founder of EpiThany and editor-in-chief of JAMA Oncology.

[email protected]

All patients receiving active cancer treatment should receive a COVID-19 vaccine and should be prioritized for vaccination, according to preliminary recommendations from the National Comprehensive Cancer Network (NCCN).

Vaccination timing considerations vary based on factors such as cancer and treatment type, and reasons for delaying vaccination in the general public also apply to cancer patients (recent COVID-19 exposure, for example).

In general, however, patients with cancer should be assigned to Centers for Disease Control and Prevention priority group 1 b/c and immunized when vaccination is available to them, the guidelines state. Exceptions to this recommendation include:

• Patients undergoing hematopoietic stem cell transplant or receiving engineered cellular therapy such as chimeric antigen receptor T-cell therapy. Vaccination should be delayed for at least 3 months in these patients to maximize vaccine efficacy. Caregivers of these patients, however, should be immunized when possible.
• Patients with hematologic malignancies who are receiving intensive cytotoxic chemotherapy, such as cytarabine- or anthracycline-based regimens for acute myeloid leukemia. Vaccination in these patients should be delayed until absolute neutrophil count recovery.
• Patients undergoing major surgery. Vaccination should occur at least a few days before or after surgery.
• Patients who have experienced a severe or immediate adverse reaction to any of the ingredients in the mRNA COVID-19 vaccines.

Conversely, vaccination should occur when available in patients with hematologic malignancies and marrow failure who are expected to have limited or no recovery, patients with hematologic malignancies who are on long-term maintenance therapy, and patients with solid tumors who are receiving cytotoxic chemotherapy, targeted therapy, checkpoint inhibitors and other immunotherapy, or radiotherapy.

Caregivers, household contacts, and other close contacts who are 16 years of age and older should be vaccinated whenever they are eligible.
 

Unique concerns in patients with cancer

The NCCN recommendations were developed to address the unique issues and concerns with respect to patients with cancer, who have an increased risk of severe illness from SARS-CoV-2 infection. But the guidelines come with a caveat: “[t]here are limited safety and efficacy data in these patients,” the NCCN emphasized in a press statement.

“Right now, there is urgent need and limited data,” Steven Pergam, MD, co-leader of the NCCN COVID-19 Vaccination Committee, said in the statement.

“Our number one goal is helping to get the vaccine to as many people as we can,” Dr. Pergam said. “That means following existing national and regional directions for prioritizing people who are more likely to face death or severe illness from COVID-19.”

Dr. Pergam, associate professor at Fred Hutchinson Cancer Research Center in Seattle, further explained that “people receiving active cancer treatment are at greater risk for worse outcomes from COVID-19, particularly if they are older and have additional comorbidities, like immunosuppression.”

NCCN’s recommendations couldn’t have come at a better time for patients with cancer, according to Nora Disis, MD, a professor at the University of Washington in Seattle.

“The NCCN’s recommendations to prioritize COVID vaccinations for cancer patients on active treatment is an important step forward in protecting our patients from the infection,” Dr. Disis said in an interview.

“Cancer patients may be at higher risk for the complications seen with infection. In addition, cancer is a disease of older people, and a good number of our patients have the comorbidities that would predict a poorer outcome if they should become sick,” Dr. Disis added. “With the correct treatment, many patients with cancer will be long-term survivors. It is important that they be protected from infection with COVID to realize their best outcome.”
 

Additional vaccine considerations

The NCCN recommendations also address several other issues of importance for cancer patients, including:

• Deprioritizing other vaccines. COVID-19 vaccines should take precedence over other vaccines because data on dual vaccination are lacking. The NCCN recommends waiting 14 days after COVID-19 vaccination to deliver other vaccines.
• Vaccinating clinical trial participants. Trial leads should be consulted to prevent protocol violations or exclusions.
• Decision-making in the setting of limited vaccine availability. The NCCN noted that decisions on allocation must be made in accordance with state and local vaccine guidance but suggests prioritizing appropriate patients on active treatment, those planning to start treatment, and those who have just completed treatment. Additional risk factors for these patients, as well as other factors associated with risk for adverse COVID-19 outcomes, should also be considered. These include advanced age, comorbidities, and adverse social and demographic factors such as poverty and limited health care access.
• The need for ongoing prevention measures. Vaccines have been shown to decrease the incidence of COVID-19 and related complications, but it remains unclear whether vaccines prevent infection and subsequent transmission. This means everyone should continue following prevention recommendations, such as wearing masks and avoiding crowds.

The NCCN stressed that these recommendations are “intended to be a living document that is constantly evolving – it will be updated rapidly whenever new data comes out, as well as any potential new vaccines that may get approved in the future.” The NCCN also noted that the advisory committee will meet regularly to refine the recommendations as needed.

Dr. Pergam disclosed relationships with Chimerix Inc., Merck & Co., Global Life Technologies Inc., and Sanofi-Aventis. Dr. Disis disclosed grants from Pfizer, Bavarian Nordisk, Janssen, and Precigen. She is the founder of EpiThany and editor-in-chief of JAMA Oncology.

[email protected]

All patients receiving active cancer treatment should receive a COVID-19 vaccine and should be prioritized for vaccination, according to preliminary recommendations from the National Comprehensive Cancer Network (NCCN).

Vaccination timing considerations vary based on factors such as cancer and treatment type, and reasons for delaying vaccination in the general public also apply to cancer patients (recent COVID-19 exposure, for example).

In general, however, patients with cancer should be assigned to Centers for Disease Control and Prevention priority group 1 b/c and immunized when vaccination is available to them, the guidelines state. Exceptions to this recommendation include:

• Patients undergoing hematopoietic stem cell transplant or receiving engineered cellular therapy such as chimeric antigen receptor T-cell therapy. Vaccination should be delayed for at least 3 months in these patients to maximize vaccine efficacy. Caregivers of these patients, however, should be immunized when possible.
• Patients with hematologic malignancies who are receiving intensive cytotoxic chemotherapy, such as cytarabine- or anthracycline-based regimens for acute myeloid leukemia. Vaccination in these patients should be delayed until absolute neutrophil count recovery.
• Patients undergoing major surgery. Vaccination should occur at least a few days before or after surgery.
• Patients who have experienced a severe or immediate adverse reaction to any of the ingredients in the mRNA COVID-19 vaccines.

Conversely, vaccination should occur when available in patients with hematologic malignancies and marrow failure who are expected to have limited or no recovery, patients with hematologic malignancies who are on long-term maintenance therapy, and patients with solid tumors who are receiving cytotoxic chemotherapy, targeted therapy, checkpoint inhibitors and other immunotherapy, or radiotherapy.

Caregivers, household contacts, and other close contacts who are 16 years of age and older should be vaccinated whenever they are eligible.
 

Unique concerns in patients with cancer

The NCCN recommendations were developed to address the unique issues and concerns with respect to patients with cancer, who have an increased risk of severe illness from SARS-CoV-2 infection. But the guidelines come with a caveat: “[t]here are limited safety and efficacy data in these patients,” the NCCN emphasized in a press statement.

“Right now, there is urgent need and limited data,” Steven Pergam, MD, co-leader of the NCCN COVID-19 Vaccination Committee, said in the statement.

“Our number one goal is helping to get the vaccine to as many people as we can,” Dr. Pergam said. “That means following existing national and regional directions for prioritizing people who are more likely to face death or severe illness from COVID-19.”

Dr. Pergam, associate professor at Fred Hutchinson Cancer Research Center in Seattle, further explained that “people receiving active cancer treatment are at greater risk for worse outcomes from COVID-19, particularly if they are older and have additional comorbidities, like immunosuppression.”

NCCN’s recommendations couldn’t have come at a better time for patients with cancer, according to Nora Disis, MD, a professor at the University of Washington in Seattle.

“The NCCN’s recommendations to prioritize COVID vaccinations for cancer patients on active treatment is an important step forward in protecting our patients from the infection,” Dr. Disis said in an interview.

“Cancer patients may be at higher risk for the complications seen with infection. In addition, cancer is a disease of older people, and a good number of our patients have the comorbidities that would predict a poorer outcome if they should become sick,” Dr. Disis added. “With the correct treatment, many patients with cancer will be long-term survivors. It is important that they be protected from infection with COVID to realize their best outcome.”
 

Additional vaccine considerations

The NCCN recommendations also address several other issues of importance for cancer patients, including:

• Deprioritizing other vaccines. COVID-19 vaccines should take precedence over other vaccines because data on dual vaccination are lacking. The NCCN recommends waiting 14 days after COVID-19 vaccination to deliver other vaccines.
• Vaccinating clinical trial participants. Trial leads should be consulted to prevent protocol violations or exclusions.
• Decision-making in the setting of limited vaccine availability. The NCCN noted that decisions on allocation must be made in accordance with state and local vaccine guidance but suggests prioritizing appropriate patients on active treatment, those planning to start treatment, and those who have just completed treatment. Additional risk factors for these patients, as well as other factors associated with risk for adverse COVID-19 outcomes, should also be considered. These include advanced age, comorbidities, and adverse social and demographic factors such as poverty and limited health care access.
• The need for ongoing prevention measures. Vaccines have been shown to decrease the incidence of COVID-19 and related complications, but it remains unclear whether vaccines prevent infection and subsequent transmission. This means everyone should continue following prevention recommendations, such as wearing masks and avoiding crowds.

The NCCN stressed that these recommendations are “intended to be a living document that is constantly evolving – it will be updated rapidly whenever new data comes out, as well as any potential new vaccines that may get approved in the future.” The NCCN also noted that the advisory committee will meet regularly to refine the recommendations as needed.

Dr. Pergam disclosed relationships with Chimerix Inc., Merck & Co., Global Life Technologies Inc., and Sanofi-Aventis. Dr. Disis disclosed grants from Pfizer, Bavarian Nordisk, Janssen, and Precigen. She is the founder of EpiThany and editor-in-chief of JAMA Oncology.

[email protected]

Emerging data support the clinical validity and use of DecisionDx-SCC as a prognostic 40-gene expression profile test for patients with high-risk squamous cell carcinoma (SCC), according to Anna A. Bar, MD.

“The incidence of SCC has been growing rapidly, and the disease-related mortality is actually more than that of melanoma,” Dr. Bar, associate professor of dermatology at Oregon Health & Science University, Portland, said during a virtual forum on cutaneous malignancies jointly presented by Postgraduate Institute for Medicine and Global Academy for Medical Education.

“Like many cancers, SCC management plans are guided by the risk of metastasis. The current staging systems, like NCCN, AJCC, or Brigham and Women’s systems, struggle to provide accurate data of the metastatic potential of an individual’s SCC,” she said. “Furthermore, the predictive accuracy of these systems in SCC is variable, and many patients who have high risk factors do not experience poor outcomes, while others initially classified as having less concerning tumors will go on to have metastatic disease. That is where new gene expression tests come into play.”

Developed by and commercially available from Castle Biosciences, DecisionDx-SCC classifies an individual SCC patient’s tumor into one of the categories: low (class 1), moderate (class 2A), or high (class 2B) biologic risk of metastasis. “We’re hoping that DecisionDx results can help make management decisions within established guidelines,” Dr. Bar said. The test is indicated for patients with high-risk features including tumor size greater than 2 cm; tumor location on the head, neck, hands, genitals, feet, or pretibial surface; immunosuppression; a rapidly growing tumor; a tumor with poorly defined borders; a tumor at the site of prior radiation or chronic inflammation; perineural invasion; poorly defined tumor grade, and a deep tumor beyond the subcutaneous fat.

One validity study and three clinical utility studies of DecisionDx-SCC have been published that include data from more than 1,100 patients (see Curr Med Res Opin. 2020 Aug;36[8]:1301-7; Curr Med Res Opin. 2020 Aug;36[8]:1295-1300, and J Drugs Dermatol. 2019 Oct 1;18[10]:980-4). “This is a work in progress,” said Dr. Bar, director of the university’s Mohs micrographic surgery and cutaneous oncology fellowship.

The test was validated in an another study, which was prospectively designed and used archival tissue from 33 independent academic and community centers, including Oregon Health & Science University. All 420 patients in the clinical validation study had one or more high-risk factors, meeting the definition of high risk by NCCN or Mohs Appropriate Use Criteria (AUC). Their mean age was 71 years, 73% were male, 99% were White, and 25% were immune deficient.

Of the 420 patients, 63 had metastasis, and 86% of metastases were located on the head and neck. About 30% of metastasized lesions had perineural involvement, 27% had invasion beyond subcutaneous fat, and metastasized lesions were about 1 cm wider compared with lesions that were not. The overall metastasis rate at 3 years was 15%, “which is similar to that seen in the medical literature for high-risk populations,” Dr. Bar said.

The median time to metastasis was 0.9 years and the 95th percentile was 2.7 years. “This means that the 3-year horizon for identifying events in this study enabled identification of most patients who eventually experienced metastatic events,” she said. In this cohort, approximately half of the metastatic events occurred around 11 months post diagnosis, which “may provide guidance about the timeline and duration of high-intensity follow-up with frequency of clinical visits and imaging for patients at highest risk within the first year.”

The positive predictive value of the DecisionDx-SCC is 52%, meaning that half of class 2B lesions will metastasize. “This compares favorably when you look at the lower positive predictive value of the other staging systems,” Dr. Bar said. “The negative predictive value is 93%, meaning there are not a lot of false negatives. This also compares favorably to the other staging systems.”

Kaplan-Meier analysis of metastasis-free survival showed strong separation between patients with class 1, class 2A, and class 2B results, Dr. Bar said. While the overall risk of metastasis in this patient cohort was 15%, the risk among those with a class 1 result was less than half of that. “Patients with a class 2A result behave similarly to those with traditional risk factors such as deep invasion and poor differentiation, having about a 20% risk of metastasis,” she said. “The class 2B result identifies the most worrisome SCCs, with a greater than 50% risk of metastasis. While the results distribution from routine clinical testing is not yet known, this large validation study of high-risk SCC revealed that approximately half of the patients were class 1, less than half were class 2A, and about 1 in 18 had a class 2B result.”

On univariate analyses with traditional risk factors and use of the Brigham and Women’s staging system, the hazard ratio (HR) for class 2A lesions was 3.2, “which is similar to deep invasion, poor differentiation, or perineural involvement,” Dr. Bar said. At the same time, the HR for class 2B lesions was 11.6, “so class 2B is the strongest predictor of metastasis. The class 2B HR remained statistically significant in the multivariate analysis and is three times higher than that of the next highest HR in this cohort. For example, a high-risk SCC with deep invasion is already two times more likely to metastasize. Adding a class 2B score would be over 14 times more likely to metastasize than a tumor with a class 1 result.”

DecisionDx-SCC test results can inform management decisions within established guidelines. For example, for a high-risk SCC patient who has a class 1 result, or low risk of metastasis, “you may proceed with surgery and clinical nodal exam, and then follow up a couple of times a year,” Dr. Bar said. “For a high-risk patient with a 2A or moderate risk result, you might proceed with surgical treatment plus consider imaging studies such as ultrasound, CT, PET CT, and consider referral to other specialties.”

For a high-risk patient with a 2B or high risk result, she continued, “you may want to proceed with imaging studies right away in addition to surgery and consider consultation with radiation oncology or medical oncology, as well as more frequent follow-up with nodal exams, because the class 2B patients have been shown to have a greater than 50% risk of metastasis.”

Global Academy for Medical Education and this news organization are owned by the same parent company.

Dr. Bar disclosed that Oregon Health & Science University has received research funding from Castle Biosciences.

[email protected]

Emerging data support the clinical validity and use of DecisionDx-SCC as a prognostic 40-gene expression profile test for patients with high-risk squamous cell carcinoma (SCC), according to Anna A. Bar, MD.

“The incidence of SCC has been growing rapidly, and the disease-related mortality is actually more than that of melanoma,” Dr. Bar, associate professor of dermatology at Oregon Health & Science University, Portland, said during a virtual forum on cutaneous malignancies jointly presented by Postgraduate Institute for Medicine and Global Academy for Medical Education.

“Like many cancers, SCC management plans are guided by the risk of metastasis. The current staging systems, like NCCN, AJCC, or Brigham and Women’s systems, struggle to provide accurate data of the metastatic potential of an individual’s SCC,” she said. “Furthermore, the predictive accuracy of these systems in SCC is variable, and many patients who have high risk factors do not experience poor outcomes, while others initially classified as having less concerning tumors will go on to have metastatic disease. That is where new gene expression tests come into play.”

Developed by and commercially available from Castle Biosciences, DecisionDx-SCC classifies an individual SCC patient’s tumor into one of the categories: low (class 1), moderate (class 2A), or high (class 2B) biologic risk of metastasis. “We’re hoping that DecisionDx results can help make management decisions within established guidelines,” Dr. Bar said. The test is indicated for patients with high-risk features including tumor size greater than 2 cm; tumor location on the head, neck, hands, genitals, feet, or pretibial surface; immunosuppression; a rapidly growing tumor; a tumor with poorly defined borders; a tumor at the site of prior radiation or chronic inflammation; perineural invasion; poorly defined tumor grade, and a deep tumor beyond the subcutaneous fat.

One validity study and three clinical utility studies of DecisionDx-SCC have been published that include data from more than 1,100 patients (see Curr Med Res Opin. 2020 Aug;36[8]:1301-7; Curr Med Res Opin. 2020 Aug;36[8]:1295-1300, and J Drugs Dermatol. 2019 Oct 1;18[10]:980-4). “This is a work in progress,” said Dr. Bar, director of the university’s Mohs micrographic surgery and cutaneous oncology fellowship.

The test was validated in an another study, which was prospectively designed and used archival tissue from 33 independent academic and community centers, including Oregon Health & Science University. All 420 patients in the clinical validation study had one or more high-risk factors, meeting the definition of high risk by NCCN or Mohs Appropriate Use Criteria (AUC). Their mean age was 71 years, 73% were male, 99% were White, and 25% were immune deficient.

Of the 420 patients, 63 had metastasis, and 86% of metastases were located on the head and neck. About 30% of metastasized lesions had perineural involvement, 27% had invasion beyond subcutaneous fat, and metastasized lesions were about 1 cm wider compared with lesions that were not. The overall metastasis rate at 3 years was 15%, “which is similar to that seen in the medical literature for high-risk populations,” Dr. Bar said.

The median time to metastasis was 0.9 years and the 95th percentile was 2.7 years. “This means that the 3-year horizon for identifying events in this study enabled identification of most patients who eventually experienced metastatic events,” she said. In this cohort, approximately half of the metastatic events occurred around 11 months post diagnosis, which “may provide guidance about the timeline and duration of high-intensity follow-up with frequency of clinical visits and imaging for patients at highest risk within the first year.”

The positive predictive value of the DecisionDx-SCC is 52%, meaning that half of class 2B lesions will metastasize. “This compares favorably when you look at the lower positive predictive value of the other staging systems,” Dr. Bar said. “The negative predictive value is 93%, meaning there are not a lot of false negatives. This also compares favorably to the other staging systems.”

Kaplan-Meier analysis of metastasis-free survival showed strong separation between patients with class 1, class 2A, and class 2B results, Dr. Bar said. While the overall risk of metastasis in this patient cohort was 15%, the risk among those with a class 1 result was less than half of that. “Patients with a class 2A result behave similarly to those with traditional risk factors such as deep invasion and poor differentiation, having about a 20% risk of metastasis,” she said. “The class 2B result identifies the most worrisome SCCs, with a greater than 50% risk of metastasis. While the results distribution from routine clinical testing is not yet known, this large validation study of high-risk SCC revealed that approximately half of the patients were class 1, less than half were class 2A, and about 1 in 18 had a class 2B result.”

On univariate analyses with traditional risk factors and use of the Brigham and Women’s staging system, the hazard ratio (HR) for class 2A lesions was 3.2, “which is similar to deep invasion, poor differentiation, or perineural involvement,” Dr. Bar said. At the same time, the HR for class 2B lesions was 11.6, “so class 2B is the strongest predictor of metastasis. The class 2B HR remained statistically significant in the multivariate analysis and is three times higher than that of the next highest HR in this cohort. For example, a high-risk SCC with deep invasion is already two times more likely to metastasize. Adding a class 2B score would be over 14 times more likely to metastasize than a tumor with a class 1 result.”

DecisionDx-SCC test results can inform management decisions within established guidelines. For example, for a high-risk SCC patient who has a class 1 result, or low risk of metastasis, “you may proceed with surgery and clinical nodal exam, and then follow up a couple of times a year,” Dr. Bar said. “For a high-risk patient with a 2A or moderate risk result, you might proceed with surgical treatment plus consider imaging studies such as ultrasound, CT, PET CT, and consider referral to other specialties.”

For a high-risk patient with a 2B or high risk result, she continued, “you may want to proceed with imaging studies right away in addition to surgery and consider consultation with radiation oncology or medical oncology, as well as more frequent follow-up with nodal exams, because the class 2B patients have been shown to have a greater than 50% risk of metastasis.”

Global Academy for Medical Education and this news organization are owned by the same parent company.

Dr. Bar disclosed that Oregon Health & Science University has received research funding from Castle Biosciences.

[email protected]

Emerging data support the clinical validity and use of DecisionDx-SCC as a prognostic 40-gene expression profile test for patients with high-risk squamous cell carcinoma (SCC), according to Anna A. Bar, MD.

“The incidence of SCC has been growing rapidly, and the disease-related mortality is actually more than that of melanoma,” Dr. Bar, associate professor of dermatology at Oregon Health & Science University, Portland, said during a virtual forum on cutaneous malignancies jointly presented by Postgraduate Institute for Medicine and Global Academy for Medical Education.

“Like many cancers, SCC management plans are guided by the risk of metastasis. The current staging systems, like NCCN, AJCC, or Brigham and Women’s systems, struggle to provide accurate data of the metastatic potential of an individual’s SCC,” she said. “Furthermore, the predictive accuracy of these systems in SCC is variable, and many patients who have high risk factors do not experience poor outcomes, while others initially classified as having less concerning tumors will go on to have metastatic disease. That is where new gene expression tests come into play.”

Developed by and commercially available from Castle Biosciences, DecisionDx-SCC classifies an individual SCC patient’s tumor into one of the categories: low (class 1), moderate (class 2A), or high (class 2B) biologic risk of metastasis. “We’re hoping that DecisionDx results can help make management decisions within established guidelines,” Dr. Bar said. The test is indicated for patients with high-risk features including tumor size greater than 2 cm; tumor location on the head, neck, hands, genitals, feet, or pretibial surface; immunosuppression; a rapidly growing tumor; a tumor with poorly defined borders; a tumor at the site of prior radiation or chronic inflammation; perineural invasion; poorly defined tumor grade, and a deep tumor beyond the subcutaneous fat.

One validity study and three clinical utility studies of DecisionDx-SCC have been published that include data from more than 1,100 patients (see Curr Med Res Opin. 2020 Aug;36[8]:1301-7; Curr Med Res Opin. 2020 Aug;36[8]:1295-1300, and J Drugs Dermatol. 2019 Oct 1;18[10]:980-4). “This is a work in progress,” said Dr. Bar, director of the university’s Mohs micrographic surgery and cutaneous oncology fellowship.

The test was validated in an another study, which was prospectively designed and used archival tissue from 33 independent academic and community centers, including Oregon Health & Science University. All 420 patients in the clinical validation study had one or more high-risk factors, meeting the definition of high risk by NCCN or Mohs Appropriate Use Criteria (AUC). Their mean age was 71 years, 73% were male, 99% were White, and 25% were immune deficient.

Of the 420 patients, 63 had metastasis, and 86% of metastases were located on the head and neck. About 30% of metastasized lesions had perineural involvement, 27% had invasion beyond subcutaneous fat, and metastasized lesions were about 1 cm wider compared with lesions that were not. The overall metastasis rate at 3 years was 15%, “which is similar to that seen in the medical literature for high-risk populations,” Dr. Bar said.

The median time to metastasis was 0.9 years and the 95th percentile was 2.7 years. “This means that the 3-year horizon for identifying events in this study enabled identification of most patients who eventually experienced metastatic events,” she said. In this cohort, approximately half of the metastatic events occurred around 11 months post diagnosis, which “may provide guidance about the timeline and duration of high-intensity follow-up with frequency of clinical visits and imaging for patients at highest risk within the first year.”

The positive predictive value of the DecisionDx-SCC is 52%, meaning that half of class 2B lesions will metastasize. “This compares favorably when you look at the lower positive predictive value of the other staging systems,” Dr. Bar said. “The negative predictive value is 93%, meaning there are not a lot of false negatives. This also compares favorably to the other staging systems.”

Kaplan-Meier analysis of metastasis-free survival showed strong separation between patients with class 1, class 2A, and class 2B results, Dr. Bar said. While the overall risk of metastasis in this patient cohort was 15%, the risk among those with a class 1 result was less than half of that. “Patients with a class 2A result behave similarly to those with traditional risk factors such as deep invasion and poor differentiation, having about a 20% risk of metastasis,” she said. “The class 2B result identifies the most worrisome SCCs, with a greater than 50% risk of metastasis. While the results distribution from routine clinical testing is not yet known, this large validation study of high-risk SCC revealed that approximately half of the patients were class 1, less than half were class 2A, and about 1 in 18 had a class 2B result.”

On univariate analyses with traditional risk factors and use of the Brigham and Women’s staging system, the hazard ratio (HR) for class 2A lesions was 3.2, “which is similar to deep invasion, poor differentiation, or perineural involvement,” Dr. Bar said. At the same time, the HR for class 2B lesions was 11.6, “so class 2B is the strongest predictor of metastasis. The class 2B HR remained statistically significant in the multivariate analysis and is three times higher than that of the next highest HR in this cohort. For example, a high-risk SCC with deep invasion is already two times more likely to metastasize. Adding a class 2B score would be over 14 times more likely to metastasize than a tumor with a class 1 result.”

DecisionDx-SCC test results can inform management decisions within established guidelines. For example, for a high-risk SCC patient who has a class 1 result, or low risk of metastasis, “you may proceed with surgery and clinical nodal exam, and then follow up a couple of times a year,” Dr. Bar said. “For a high-risk patient with a 2A or moderate risk result, you might proceed with surgical treatment plus consider imaging studies such as ultrasound, CT, PET CT, and consider referral to other specialties.”

For a high-risk patient with a 2B or high risk result, she continued, “you may want to proceed with imaging studies right away in addition to surgery and consider consultation with radiation oncology or medical oncology, as well as more frequent follow-up with nodal exams, because the class 2B patients have been shown to have a greater than 50% risk of metastasis.”

Global Academy for Medical Education and this news organization are owned by the same parent company.

Dr. Bar disclosed that Oregon Health & Science University has received research funding from Castle Biosciences.

[email protected]

Even in the most experienced hands, dermoscopy poses a challenge when the usual pigment clues are lacking to help distinguish melanoma from amelanotic melanoma and pigmented basal cell carcinoma (BCC) from nonpigmented BCC.

Copyright Dr. Jennifer A. Stein

“For me, pink lesions are challenging,” Jennifer A. Stein, MD, PhD, said during the virtual Orlando Dermatology Aesthetic and Clinical Conference. “How can dermoscopy help us distinguish between Spitz nevus, melanoma, clear cell acanthoma, psoriasis, basal cell carcinoma, and squamous cell carcinoma?”

Dr. Stein, professor of dermatology at New York University, offered four tips. First, look for the shiny white perpendicular lines, otherwise known as the chrysalis or crystalline pattern. “You can only see this feature when you’re looking with polarized light,” she said. “This is why you want a dermatoscope that has polarized light, and better yet, one that you’re able to turn on and off, the hybrid kind, because then you can convince yourself that you’re looking at this feature, because it blinks on and off.”

The differential diagnosis for white shiny perpendicular lines includes dermatofibroma/scars (which is most common), Spitz and atypical genital nevi, BCC, and melanoma. “Dermatofibromas sometimes have white circles or rings in the center,” Dr. Stein said. “In BCC, the lines aren’t always perpendicular. Sometimes it’s more of a blotch or strands.”

A second tip for managing a pink lesion on dermoscopy is to look for any brown color. “When you see that combo together you have to worry,” she said. “When you see pigment network on dermoscopy, you have to put melanoma in your differential. If you see shiny white lines in something that is melanocytic, there’s a 98% specificity for melanoma.”

A third tip she offered for managing pink lesions is to check the blood vessels for clues. “For years, I was just naming the vessels based on making the diagnosis and then deciding, ‘that’s a basal cell carcinoma; those must be branching vessels,’ ” said Dr. Stein, who manages NYU’s medical dermatology faculty group practice.

However, blood vessel patterns differ. For example, branching or arborizing vessels are suggestive of BCC. “These vessels are very crisp-looking on dermoscopy,” she said. “They’re all in the same plane of focus and they look like they were drawn in with a fine point marker. That’s different from other blood vessel patterns.” She also pointed out that superficial basal cells have short, fine telangiectasias. “When you put on the polarized light, the clue is the white, shiny structures,” she said.

Dotted vessels, meanwhile, appear on dermoscopy as small red dots aligned perpendicular to the skin surface. The differential includes inflammatory lesions like psoriasis, stasis, and trauma; clear cell acanthoma (characterized by a “string of pearls” arrangement), nevi, and melanoma. “I find dermoscopy most useful in diagnosing SCC – especially squamous cell in situ,” she said. “Important clinical clues suggestive of SCC or melanoma include a solitary lesion, it’s new, it’s growing, and it’s not going away with a topical steroid.”

An additional pattern to be aware of are hairpin vessels, which are looped and feature a sharp bend at one end. These are often seen in seborrheic keratoses. “You can’t count on the hairpin vessels alone, because you can see this in anything keratotic, such as in keratoacanthoma (at the periphery with a yellow keratotic center), warts, SCC, BCC, as well as in dermal nevi and Spitz nevi,” said Dr. Stein, who recommended dermoscopedia.org as resource.

Comma vessels, meanwhile, appear in dermal or compound nevi. She described these as “slightly curved vessels that are much less in focus than branched vessels, because they come in and out of the plane of focus,” she said. “If you put your dermatoscope on top of the nevus and wobble it around you can appreciate the curve. If you look at it from the side, it looks like a curve. If you look at it straight on it will look more like a line. If you look at from the end it will look like a dot.”

Another vessel type she discussed are linear irregular and polymorphous vessels, which she described as “any combination of different types of vessels. We get most worried when we see dotted and linear irregular vessels together. In that case, you worry about melanoma. These can also be seen in nevi and other tumors, such as BCC.”

Dr. Stein’s fourth tip of the presentation was a reminder to consider dermoscopy as one piece of the clinical exam. “Always think about the lesion in context of the rest of the clinical picture and history,” she said. “Don’t get discouraged if it’s hard; just keep practicing. Look for any brown and use your clinical clues to put together to make the right decision.”

She disclosed that NYU receives compensation from MoleSafe for her telemedicine dermoscopic diagnoses.

[email protected]

Even in the most experienced hands, dermoscopy poses a challenge when the usual pigment clues are lacking to help distinguish melanoma from amelanotic melanoma and pigmented basal cell carcinoma (BCC) from nonpigmented BCC.

Copyright Dr. Jennifer A. Stein

“For me, pink lesions are challenging,” Jennifer A. Stein, MD, PhD, said during the virtual Orlando Dermatology Aesthetic and Clinical Conference. “How can dermoscopy help us distinguish between Spitz nevus, melanoma, clear cell acanthoma, psoriasis, basal cell carcinoma, and squamous cell carcinoma?”

Dr. Stein, professor of dermatology at New York University, offered four tips. First, look for the shiny white perpendicular lines, otherwise known as the chrysalis or crystalline pattern. “You can only see this feature when you’re looking with polarized light,” she said. “This is why you want a dermatoscope that has polarized light, and better yet, one that you’re able to turn on and off, the hybrid kind, because then you can convince yourself that you’re looking at this feature, because it blinks on and off.”

The differential diagnosis for white shiny perpendicular lines includes dermatofibroma/scars (which is most common), Spitz and atypical genital nevi, BCC, and melanoma. “Dermatofibromas sometimes have white circles or rings in the center,” Dr. Stein said. “In BCC, the lines aren’t always perpendicular. Sometimes it’s more of a blotch or strands.”

A second tip for managing a pink lesion on dermoscopy is to look for any brown color. “When you see that combo together you have to worry,” she said. “When you see pigment network on dermoscopy, you have to put melanoma in your differential. If you see shiny white lines in something that is melanocytic, there’s a 98% specificity for melanoma.”

A third tip she offered for managing pink lesions is to check the blood vessels for clues. “For years, I was just naming the vessels based on making the diagnosis and then deciding, ‘that’s a basal cell carcinoma; those must be branching vessels,’ ” said Dr. Stein, who manages NYU’s medical dermatology faculty group practice.

However, blood vessel patterns differ. For example, branching or arborizing vessels are suggestive of BCC. “These vessels are very crisp-looking on dermoscopy,” she said. “They’re all in the same plane of focus and they look like they were drawn in with a fine point marker. That’s different from other blood vessel patterns.” She also pointed out that superficial basal cells have short, fine telangiectasias. “When you put on the polarized light, the clue is the white, shiny structures,” she said.

Dotted vessels, meanwhile, appear on dermoscopy as small red dots aligned perpendicular to the skin surface. The differential includes inflammatory lesions like psoriasis, stasis, and trauma; clear cell acanthoma (characterized by a “string of pearls” arrangement), nevi, and melanoma. “I find dermoscopy most useful in diagnosing SCC – especially squamous cell in situ,” she said. “Important clinical clues suggestive of SCC or melanoma include a solitary lesion, it’s new, it’s growing, and it’s not going away with a topical steroid.”

An additional pattern to be aware of are hairpin vessels, which are looped and feature a sharp bend at one end. These are often seen in seborrheic keratoses. “You can’t count on the hairpin vessels alone, because you can see this in anything keratotic, such as in keratoacanthoma (at the periphery with a yellow keratotic center), warts, SCC, BCC, as well as in dermal nevi and Spitz nevi,” said Dr. Stein, who recommended dermoscopedia.org as resource.

Comma vessels, meanwhile, appear in dermal or compound nevi. She described these as “slightly curved vessels that are much less in focus than branched vessels, because they come in and out of the plane of focus,” she said. “If you put your dermatoscope on top of the nevus and wobble it around you can appreciate the curve. If you look at it from the side, it looks like a curve. If you look at it straight on it will look more like a line. If you look at from the end it will look like a dot.”

Another vessel type she discussed are linear irregular and polymorphous vessels, which she described as “any combination of different types of vessels. We get most worried when we see dotted and linear irregular vessels together. In that case, you worry about melanoma. These can also be seen in nevi and other tumors, such as BCC.”

Dr. Stein’s fourth tip of the presentation was a reminder to consider dermoscopy as one piece of the clinical exam. “Always think about the lesion in context of the rest of the clinical picture and history,” she said. “Don’t get discouraged if it’s hard; just keep practicing. Look for any brown and use your clinical clues to put together to make the right decision.”

She disclosed that NYU receives compensation from MoleSafe for her telemedicine dermoscopic diagnoses.

[email protected]

Even in the most experienced hands, dermoscopy poses a challenge when the usual pigment clues are lacking to help distinguish melanoma from amelanotic melanoma and pigmented basal cell carcinoma (BCC) from nonpigmented BCC.

Copyright Dr. Jennifer A. Stein

“For me, pink lesions are challenging,” Jennifer A. Stein, MD, PhD, said during the virtual Orlando Dermatology Aesthetic and Clinical Conference. “How can dermoscopy help us distinguish between Spitz nevus, melanoma, clear cell acanthoma, psoriasis, basal cell carcinoma, and squamous cell carcinoma?”

Dr. Stein, professor of dermatology at New York University, offered four tips. First, look for the shiny white perpendicular lines, otherwise known as the chrysalis or crystalline pattern. “You can only see this feature when you’re looking with polarized light,” she said. “This is why you want a dermatoscope that has polarized light, and better yet, one that you’re able to turn on and off, the hybrid kind, because then you can convince yourself that you’re looking at this feature, because it blinks on and off.”

The differential diagnosis for white shiny perpendicular lines includes dermatofibroma/scars (which is most common), Spitz and atypical genital nevi, BCC, and melanoma. “Dermatofibromas sometimes have white circles or rings in the center,” Dr. Stein said. “In BCC, the lines aren’t always perpendicular. Sometimes it’s more of a blotch or strands.”

A second tip for managing a pink lesion on dermoscopy is to look for any brown color. “When you see that combo together you have to worry,” she said. “When you see pigment network on dermoscopy, you have to put melanoma in your differential. If you see shiny white lines in something that is melanocytic, there’s a 98% specificity for melanoma.”

A third tip she offered for managing pink lesions is to check the blood vessels for clues. “For years, I was just naming the vessels based on making the diagnosis and then deciding, ‘that’s a basal cell carcinoma; those must be branching vessels,’ ” said Dr. Stein, who manages NYU’s medical dermatology faculty group practice.

However, blood vessel patterns differ. For example, branching or arborizing vessels are suggestive of BCC. “These vessels are very crisp-looking on dermoscopy,” she said. “They’re all in the same plane of focus and they look like they were drawn in with a fine point marker. That’s different from other blood vessel patterns.” She also pointed out that superficial basal cells have short, fine telangiectasias. “When you put on the polarized light, the clue is the white, shiny structures,” she said.

Dotted vessels, meanwhile, appear on dermoscopy as small red dots aligned perpendicular to the skin surface. The differential includes inflammatory lesions like psoriasis, stasis, and trauma; clear cell acanthoma (characterized by a “string of pearls” arrangement), nevi, and melanoma. “I find dermoscopy most useful in diagnosing SCC – especially squamous cell in situ,” she said. “Important clinical clues suggestive of SCC or melanoma include a solitary lesion, it’s new, it’s growing, and it’s not going away with a topical steroid.”

An additional pattern to be aware of are hairpin vessels, which are looped and feature a sharp bend at one end. These are often seen in seborrheic keratoses. “You can’t count on the hairpin vessels alone, because you can see this in anything keratotic, such as in keratoacanthoma (at the periphery with a yellow keratotic center), warts, SCC, BCC, as well as in dermal nevi and Spitz nevi,” said Dr. Stein, who recommended dermoscopedia.org as resource.

Comma vessels, meanwhile, appear in dermal or compound nevi. She described these as “slightly curved vessels that are much less in focus than branched vessels, because they come in and out of the plane of focus,” she said. “If you put your dermatoscope on top of the nevus and wobble it around you can appreciate the curve. If you look at it from the side, it looks like a curve. If you look at it straight on it will look more like a line. If you look at from the end it will look like a dot.”

Another vessel type she discussed are linear irregular and polymorphous vessels, which she described as “any combination of different types of vessels. We get most worried when we see dotted and linear irregular vessels together. In that case, you worry about melanoma. These can also be seen in nevi and other tumors, such as BCC.”

Dr. Stein’s fourth tip of the presentation was a reminder to consider dermoscopy as one piece of the clinical exam. “Always think about the lesion in context of the rest of the clinical picture and history,” she said. “Don’t get discouraged if it’s hard; just keep practicing. Look for any brown and use your clinical clues to put together to make the right decision.”

She disclosed that NYU receives compensation from MoleSafe for her telemedicine dermoscopic diagnoses.

[email protected]

To the Editor:

Pembrolizumab, a humanized monoclonal anti–programmed cell death protein 1 (PD-1) antibody, acts by blocking negative immune regulators such as PD-1.¹ Since its approval by the US Food and Drug Administration in 2014, the use of PD-1 inhibitors such as pembrolizumab has dramatically increased, and they are now the standard of care for cancers such as melanoma, lung cancer, and renal cell carcinoma.^2,3 With increased use comes a better understanding of the cutaneous adverse effects that may occur. To date, almost 50% of patients treated with PD-1 inhibitors will develop an adverse cutaneous reaction.⁴ Thus far, cases of patients developing vitiligo, bullous pemphigoid, psoriasis, granulomatous skin reactions, severe cutaneous reactions (ie, toxic epidermal necrolysis), lupus erythematosus, and lichenoid reactions have been described.^3,5,6 There are fewer than 30 documented cases of lichenoid reactions due to anti–PD-1 treatment described in the literature, increasing the importance of case reports to demonstrate a full range of cutaneous findings.³ We present a case of a reaction to pembrolizumab with an eruption of lichenoid papules predominantly involving the hands and feet as well as nail changes.

A 60-year-old man with ocular melanoma metastatic to the right lung, transverse colon, and right axillary lymph nodes presented with a chief concern of growing skin lesions present for 6 weeks on the hands and feet. The lesions were tender to the touch and occasionally drained a clear fluid. He also reported nail fragility. Of note, the patient was being treated for metastatic melanoma with pembrolizumab infusions every 3 weeks, which started 6 weeks prior to the onset of the eruption. 

Physical examination demonstrated lichenoid papules on the dorsal and ventral aspects of the hands and feet (Figure 1), as well as longitudinal ridging on numerous fingernails and mild koilonychia. A punch biopsy revealed lichenoid interface dermatitis with irregular epidermal hyperplasia (Figure 2). A diagnosis of hypertrophic lichen planus–like drug eruption in response to pembrolizumab was made and clobetasol cream was prescribed.

At 1-month follow-up, the patient reported notable improvement with clobetasol, and he was transitioned to tacrolimus ointment 0.1%. He continued to improve until a month later when he reported new lesions arising a week after a pembrolizumab infusion. He continued to use clobetasol cream for flares and tacrolimus ointment for maintenance.

Almost 3 months after the initial visit, the patient presented with inflammation around his right third fingernail of 1 week’s duration, with more notable fragility than his other nails. No trauma was described, and the nail abnormality was attributed to pembrolizumab. Clobetasol cream and biotin 3 mg daily resulted in improvement, and no other nails were affected in a similar way.

Programmed cell death protein 1 blockers are associated with a variety of adverse events including hypothyroidism, gastrointestinal abnormalities, fatigue, and skin disorders.⁷ In one study (N=83), cutaneous adverse drug events were found to occur in 42% (35/83) of patients following pembrolizumab therapy, with the most common cutaneous lesions being maculopapular eruptions (29% [24/83]), pruritus (12% [10/83]), and hypopigmentation (8% [7/83]).⁵

A total of 29 cases of lichenoid dermatitis following anti–PD-1 therapy have been described in the literature.³ Cases range from an eruption of photodistributed hyperkeratotic papules and plaques to hypertrophic vesiculobullous lesions.^3,6 Suggested pathophysiology involves blocking the interaction of programmed death ligand 1 on keratinocytes with PD-1 on T cells.³ Management typically includes topical or systemic steroids. Cyclosporine and acitretin also have been successful in a small number of patients. Most patients continue anti–PD-1 treatment with systemic therapy.³

Our patient represents a similar lichenoid eruption; however, the distribution on the dorsal and ventral aspects of the hands and feet as well as nail dystrophy make the presentation unique. Anticancer drugs that increase the T-cell immune response by altering the complex signaling among T cells, antigen-presenting cells, and tumor cells have been associated with cutaneous eruptions. Although the exact mechanism is still not fully understood, clinical suspicion of a pembrolizumab reaction should remain high on the differential in the setting of hyperkeratotic papules in association with anti–PD-1 therapy.

To the Editor:

Pembrolizumab, a humanized monoclonal anti–programmed cell death protein 1 (PD-1) antibody, acts by blocking negative immune regulators such as PD-1.¹ Since its approval by the US Food and Drug Administration in 2014, the use of PD-1 inhibitors such as pembrolizumab has dramatically increased, and they are now the standard of care for cancers such as melanoma, lung cancer, and renal cell carcinoma.^2,3 With increased use comes a better understanding of the cutaneous adverse effects that may occur. To date, almost 50% of patients treated with PD-1 inhibitors will develop an adverse cutaneous reaction.⁴ Thus far, cases of patients developing vitiligo, bullous pemphigoid, psoriasis, granulomatous skin reactions, severe cutaneous reactions (ie, toxic epidermal necrolysis), lupus erythematosus, and lichenoid reactions have been described.^3,5,6 There are fewer than 30 documented cases of lichenoid reactions due to anti–PD-1 treatment described in the literature, increasing the importance of case reports to demonstrate a full range of cutaneous findings.³ We present a case of a reaction to pembrolizumab with an eruption of lichenoid papules predominantly involving the hands and feet as well as nail changes.

A 60-year-old man with ocular melanoma metastatic to the right lung, transverse colon, and right axillary lymph nodes presented with a chief concern of growing skin lesions present for 6 weeks on the hands and feet. The lesions were tender to the touch and occasionally drained a clear fluid. He also reported nail fragility. Of note, the patient was being treated for metastatic melanoma with pembrolizumab infusions every 3 weeks, which started 6 weeks prior to the onset of the eruption. 

Physical examination demonstrated lichenoid papules on the dorsal and ventral aspects of the hands and feet (Figure 1), as well as longitudinal ridging on numerous fingernails and mild koilonychia. A punch biopsy revealed lichenoid interface dermatitis with irregular epidermal hyperplasia (Figure 2). A diagnosis of hypertrophic lichen planus–like drug eruption in response to pembrolizumab was made and clobetasol cream was prescribed.

At 1-month follow-up, the patient reported notable improvement with clobetasol, and he was transitioned to tacrolimus ointment 0.1%. He continued to improve until a month later when he reported new lesions arising a week after a pembrolizumab infusion. He continued to use clobetasol cream for flares and tacrolimus ointment for maintenance.

Almost 3 months after the initial visit, the patient presented with inflammation around his right third fingernail of 1 week’s duration, with more notable fragility than his other nails. No trauma was described, and the nail abnormality was attributed to pembrolizumab. Clobetasol cream and biotin 3 mg daily resulted in improvement, and no other nails were affected in a similar way.

Programmed cell death protein 1 blockers are associated with a variety of adverse events including hypothyroidism, gastrointestinal abnormalities, fatigue, and skin disorders.⁷ In one study (N=83), cutaneous adverse drug events were found to occur in 42% (35/83) of patients following pembrolizumab therapy, with the most common cutaneous lesions being maculopapular eruptions (29% [24/83]), pruritus (12% [10/83]), and hypopigmentation (8% [7/83]).⁵

A total of 29 cases of lichenoid dermatitis following anti–PD-1 therapy have been described in the literature.³ Cases range from an eruption of photodistributed hyperkeratotic papules and plaques to hypertrophic vesiculobullous lesions.^3,6 Suggested pathophysiology involves blocking the interaction of programmed death ligand 1 on keratinocytes with PD-1 on T cells.³ Management typically includes topical or systemic steroids. Cyclosporine and acitretin also have been successful in a small number of patients. Most patients continue anti–PD-1 treatment with systemic therapy.³

Our patient represents a similar lichenoid eruption; however, the distribution on the dorsal and ventral aspects of the hands and feet as well as nail dystrophy make the presentation unique. Anticancer drugs that increase the T-cell immune response by altering the complex signaling among T cells, antigen-presenting cells, and tumor cells have been associated with cutaneous eruptions. Although the exact mechanism is still not fully understood, clinical suspicion of a pembrolizumab reaction should remain high on the differential in the setting of hyperkeratotic papules in association with anti–PD-1 therapy.

To the Editor:

Pembrolizumab, a humanized monoclonal anti–programmed cell death protein 1 (PD-1) antibody, acts by blocking negative immune regulators such as PD-1.¹ Since its approval by the US Food and Drug Administration in 2014, the use of PD-1 inhibitors such as pembrolizumab has dramatically increased, and they are now the standard of care for cancers such as melanoma, lung cancer, and renal cell carcinoma.^2,3 With increased use comes a better understanding of the cutaneous adverse effects that may occur. To date, almost 50% of patients treated with PD-1 inhibitors will develop an adverse cutaneous reaction.⁴ Thus far, cases of patients developing vitiligo, bullous pemphigoid, psoriasis, granulomatous skin reactions, severe cutaneous reactions (ie, toxic epidermal necrolysis), lupus erythematosus, and lichenoid reactions have been described.^3,5,6 There are fewer than 30 documented cases of lichenoid reactions due to anti–PD-1 treatment described in the literature, increasing the importance of case reports to demonstrate a full range of cutaneous findings.³ We present a case of a reaction to pembrolizumab with an eruption of lichenoid papules predominantly involving the hands and feet as well as nail changes.

A 60-year-old man with ocular melanoma metastatic to the right lung, transverse colon, and right axillary lymph nodes presented with a chief concern of growing skin lesions present for 6 weeks on the hands and feet. The lesions were tender to the touch and occasionally drained a clear fluid. He also reported nail fragility. Of note, the patient was being treated for metastatic melanoma with pembrolizumab infusions every 3 weeks, which started 6 weeks prior to the onset of the eruption. 

Physical examination demonstrated lichenoid papules on the dorsal and ventral aspects of the hands and feet (Figure 1), as well as longitudinal ridging on numerous fingernails and mild koilonychia. A punch biopsy revealed lichenoid interface dermatitis with irregular epidermal hyperplasia (Figure 2). A diagnosis of hypertrophic lichen planus–like drug eruption in response to pembrolizumab was made and clobetasol cream was prescribed.

At 1-month follow-up, the patient reported notable improvement with clobetasol, and he was transitioned to tacrolimus ointment 0.1%. He continued to improve until a month later when he reported new lesions arising a week after a pembrolizumab infusion. He continued to use clobetasol cream for flares and tacrolimus ointment for maintenance.

Almost 3 months after the initial visit, the patient presented with inflammation around his right third fingernail of 1 week’s duration, with more notable fragility than his other nails. No trauma was described, and the nail abnormality was attributed to pembrolizumab. Clobetasol cream and biotin 3 mg daily resulted in improvement, and no other nails were affected in a similar way.

Programmed cell death protein 1 blockers are associated with a variety of adverse events including hypothyroidism, gastrointestinal abnormalities, fatigue, and skin disorders.⁷ In one study (N=83), cutaneous adverse drug events were found to occur in 42% (35/83) of patients following pembrolizumab therapy, with the most common cutaneous lesions being maculopapular eruptions (29% [24/83]), pruritus (12% [10/83]), and hypopigmentation (8% [7/83]).⁵

A total of 29 cases of lichenoid dermatitis following anti–PD-1 therapy have been described in the literature.³ Cases range from an eruption of photodistributed hyperkeratotic papules and plaques to hypertrophic vesiculobullous lesions.^3,6 Suggested pathophysiology involves blocking the interaction of programmed death ligand 1 on keratinocytes with PD-1 on T cells.³ Management typically includes topical or systemic steroids. Cyclosporine and acitretin also have been successful in a small number of patients. Most patients continue anti–PD-1 treatment with systemic therapy.³

Our patient represents a similar lichenoid eruption; however, the distribution on the dorsal and ventral aspects of the hands and feet as well as nail dystrophy make the presentation unique. Anticancer drugs that increase the T-cell immune response by altering the complex signaling among T cells, antigen-presenting cells, and tumor cells have been associated with cutaneous eruptions. Although the exact mechanism is still not fully understood, clinical suspicion of a pembrolizumab reaction should remain high on the differential in the setting of hyperkeratotic papules in association with anti–PD-1 therapy.

The coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome novel coronavirus 2 (SARS-CoV-2), has presented a unique challenge to providing essential care to patients. Increased demand for health care workers and medical supplies, in addition to the risk for COVID-19 infection and asymptomatic transmission of SARS-CoV-2 among health care workers and patients, prompted the delay of nonessential services during the surge of cases this summer.¹ Key considerations for continuing operation included current and projected COVID-19 cases in the region, ability to implement telehealth, staffing availability, personal protective equipment availability, and office capacity.² Providing care that is deemed essential often was determined by the urgency of the treatment or service.

The Centers for Medicare & Medicaid Services outlined a strategy to stratify patients, based on level of acuity, during the COVID-19 surge³:

• Low-acuity treatments or services: includes routine primary, specialty, or preventive care visits. They should be postponed; telehealth follow-ups should be considered.
• Intermediate-acuity treatments or services: includes pediatric and neonatal care, follow-up visits for existing conditions, and evaluation of new symptoms (including those consistent with COVID-19). These services should initially be evaluated using telehealth, then triaged to the appropriate site and level of care.
• High-acuity treatments or services: address symptoms consistent with COVID-19 or other severe disease, of which the lack of in-person evaluation would result in harm to the patient.

Employees in hospitals and health care clinics were classified as essential, but dermatologists were not given explicit direction regarding clinic operation. Many practices have restricted services, especially those in an area of higher COVID-19 prevalence. However, the challenge of determining day-to-day operation may have been left to the provider in most cases.⁴ As many states in the United States continue to relax restrictions, total cases and the rate of positivity of COVID-19 have been sharply rising again, after months of decline,⁵ which suggests increased transmission of SARS-CoV-2 and potential resurgence of the high case burden on our health care system. Furthermore, a lack of a widely distributed vaccine or herd immunity suggests we will need to take many of the same precautions as in the first surge.⁶

In general, patients with cancer have been found to be at greater risk for adverse outcomes and mortality after COVID-19.⁷ Therefore, resource rationing is particularly concerning for patients with skin cancer, including melanoma, Merkel cell carcinoma, mycosis fungoides, and keratinocyte carcinoma. Triaging patients based on level of acuity, type of skin cancer, disease burden, host immunosuppression, and risk for progression must be carefully considered in this population.² Treatment and follow-up present additional challenges.

Guidelines provided by the National Comprehensive Cancer Network (NCCN) and the European Society for Medical Oncology (ESMO) elaborated on key considerations for the treatment of melanoma, keratinocyte carcinoma, and Merkel cell carcinoma during the COVID-19 pandemic.^8-10 Guidelines from the NCCN concentrated on clear divisions between disease stages to determine provider response. Guidelines for melanoma patients proposed by the ESMO assign tiers by value-based priority in various treatment settings, which offered flexibility to providers as the COVID-19 landscape continued to change. Recommendations from the NCCN and ESMO are summarized in Tables 1 to 5.

Tips for Performing Dermatologic Surgery

Careful consideration should be made to protect both the patient and staff during office-based excisional surgery during the COVID-19 pandemic. To minimize the risk of transmission of SARS-CoV-2, patients and staff should (1) be screened for symptoms of COVID-19 at least 48 hours prior to entering the office via telephone screening questions, and (2) follow proper hygiene and contact procedures once entering the office. Consider obtaining a nasal polymerase chain reaction swab or saliva test 48 hours prior to the procedure if the patient is undergoing a head and neck procedure or there is risk for transmission.

Guidelines from the ESMO recommended that all patients undergoing surgery or therapy should be swabbed for SARS-CoV-2 before each treatment.¹¹ Patients should wear a mask, remain 6-feet apart in the waiting room, and avoid touching objects until they enter the procedure room. Objects that the patient must touch, such as pens, should be cleaned immediately after such contact with either alcohol or soap and water for 20 seconds.

Office capacity should be reduced by allowing no more than 1 person to accompany the patient and ensuring the presence of only the minimum staff needed for the procedure. Staff who are deemed necessary should wear a mask continuously and gloves during patient contact.

Once in the procedure room, providers might be at elevated risk of contracting COVID-19 or transmitting SARS-CoV-2. A properly fitted N95 respirator and a face shield are recommended, especially for facial cases. N95 respirators can be reused by following the latest Centers for Disease Control and Prevention recommendations for reuse and decontamination techniques,¹³ which may include protecting the N95 respirator with a surgical mask and storing it in a paper bag when not in use. Consider testing asymptomatic patients in facial cases when they cannot wear a mask.

Steps should be taken to reduce in-person visits. Dissolving sutures can help avoid return visits. Follow-up visits and postprocedural questions should be managed by telehealth. However, patients with a high-risk underlying conditions (eg, posttransplantation, immunosuppressed) should continue to obtain regular skin checks because they are at higher risk for more aggressive malignancies, such as Merkel cell carcinoma.

Conclusion

The future trajectory of the COVID-19 pandemic is uncertain. Dermatologists should continue providing care for patients with skin cancer while mitigating the risk for COVID-19 infection and transmission of SARS-CoV-2. Guidelines provided by the NCCN and ESMO should help providers triage patients. Decisions should be made case by case, keeping in mind the availability of resources and practicing in compliance with local guidance.

The coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome novel coronavirus 2 (SARS-CoV-2), has presented a unique challenge to providing essential care to patients. Increased demand for health care workers and medical supplies, in addition to the risk for COVID-19 infection and asymptomatic transmission of SARS-CoV-2 among health care workers and patients, prompted the delay of nonessential services during the surge of cases this summer.¹ Key considerations for continuing operation included current and projected COVID-19 cases in the region, ability to implement telehealth, staffing availability, personal protective equipment availability, and office capacity.² Providing care that is deemed essential often was determined by the urgency of the treatment or service.

The Centers for Medicare & Medicaid Services outlined a strategy to stratify patients, based on level of acuity, during the COVID-19 surge³:

• Low-acuity treatments or services: includes routine primary, specialty, or preventive care visits. They should be postponed; telehealth follow-ups should be considered.
• Intermediate-acuity treatments or services: includes pediatric and neonatal care, follow-up visits for existing conditions, and evaluation of new symptoms (including those consistent with COVID-19). These services should initially be evaluated using telehealth, then triaged to the appropriate site and level of care.
• High-acuity treatments or services: address symptoms consistent with COVID-19 or other severe disease, of which the lack of in-person evaluation would result in harm to the patient.

Employees in hospitals and health care clinics were classified as essential, but dermatologists were not given explicit direction regarding clinic operation. Many practices have restricted services, especially those in an area of higher COVID-19 prevalence. However, the challenge of determining day-to-day operation may have been left to the provider in most cases.⁴ As many states in the United States continue to relax restrictions, total cases and the rate of positivity of COVID-19 have been sharply rising again, after months of decline,⁵ which suggests increased transmission of SARS-CoV-2 and potential resurgence of the high case burden on our health care system. Furthermore, a lack of a widely distributed vaccine or herd immunity suggests we will need to take many of the same precautions as in the first surge.⁶

In general, patients with cancer have been found to be at greater risk for adverse outcomes and mortality after COVID-19.⁷ Therefore, resource rationing is particularly concerning for patients with skin cancer, including melanoma, Merkel cell carcinoma, mycosis fungoides, and keratinocyte carcinoma. Triaging patients based on level of acuity, type of skin cancer, disease burden, host immunosuppression, and risk for progression must be carefully considered in this population.² Treatment and follow-up present additional challenges.

Guidelines provided by the National Comprehensive Cancer Network (NCCN) and the European Society for Medical Oncology (ESMO) elaborated on key considerations for the treatment of melanoma, keratinocyte carcinoma, and Merkel cell carcinoma during the COVID-19 pandemic.^8-10 Guidelines from the NCCN concentrated on clear divisions between disease stages to determine provider response. Guidelines for melanoma patients proposed by the ESMO assign tiers by value-based priority in various treatment settings, which offered flexibility to providers as the COVID-19 landscape continued to change. Recommendations from the NCCN and ESMO are summarized in Tables 1 to 5.

Tips for Performing Dermatologic Surgery

Careful consideration should be made to protect both the patient and staff during office-based excisional surgery during the COVID-19 pandemic. To minimize the risk of transmission of SARS-CoV-2, patients and staff should (1) be screened for symptoms of COVID-19 at least 48 hours prior to entering the office via telephone screening questions, and (2) follow proper hygiene and contact procedures once entering the office. Consider obtaining a nasal polymerase chain reaction swab or saliva test 48 hours prior to the procedure if the patient is undergoing a head and neck procedure or there is risk for transmission.

Guidelines from the ESMO recommended that all patients undergoing surgery or therapy should be swabbed for SARS-CoV-2 before each treatment.¹¹ Patients should wear a mask, remain 6-feet apart in the waiting room, and avoid touching objects until they enter the procedure room. Objects that the patient must touch, such as pens, should be cleaned immediately after such contact with either alcohol or soap and water for 20 seconds.

Office capacity should be reduced by allowing no more than 1 person to accompany the patient and ensuring the presence of only the minimum staff needed for the procedure. Staff who are deemed necessary should wear a mask continuously and gloves during patient contact.

Once in the procedure room, providers might be at elevated risk of contracting COVID-19 or transmitting SARS-CoV-2. A properly fitted N95 respirator and a face shield are recommended, especially for facial cases. N95 respirators can be reused by following the latest Centers for Disease Control and Prevention recommendations for reuse and decontamination techniques,¹³ which may include protecting the N95 respirator with a surgical mask and storing it in a paper bag when not in use. Consider testing asymptomatic patients in facial cases when they cannot wear a mask.

Steps should be taken to reduce in-person visits. Dissolving sutures can help avoid return visits. Follow-up visits and postprocedural questions should be managed by telehealth. However, patients with a high-risk underlying conditions (eg, posttransplantation, immunosuppressed) should continue to obtain regular skin checks because they are at higher risk for more aggressive malignancies, such as Merkel cell carcinoma.

Conclusion

The future trajectory of the COVID-19 pandemic is uncertain. Dermatologists should continue providing care for patients with skin cancer while mitigating the risk for COVID-19 infection and transmission of SARS-CoV-2. Guidelines provided by the NCCN and ESMO should help providers triage patients. Decisions should be made case by case, keeping in mind the availability of resources and practicing in compliance with local guidance.

The coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome novel coronavirus 2 (SARS-CoV-2), has presented a unique challenge to providing essential care to patients. Increased demand for health care workers and medical supplies, in addition to the risk for COVID-19 infection and asymptomatic transmission of SARS-CoV-2 among health care workers and patients, prompted the delay of nonessential services during the surge of cases this summer.¹ Key considerations for continuing operation included current and projected COVID-19 cases in the region, ability to implement telehealth, staffing availability, personal protective equipment availability, and office capacity.² Providing care that is deemed essential often was determined by the urgency of the treatment or service.

The Centers for Medicare & Medicaid Services outlined a strategy to stratify patients, based on level of acuity, during the COVID-19 surge³:

• Low-acuity treatments or services: includes routine primary, specialty, or preventive care visits. They should be postponed; telehealth follow-ups should be considered.
• Intermediate-acuity treatments or services: includes pediatric and neonatal care, follow-up visits for existing conditions, and evaluation of new symptoms (including those consistent with COVID-19). These services should initially be evaluated using telehealth, then triaged to the appropriate site and level of care.
• High-acuity treatments or services: address symptoms consistent with COVID-19 or other severe disease, of which the lack of in-person evaluation would result in harm to the patient.

Employees in hospitals and health care clinics were classified as essential, but dermatologists were not given explicit direction regarding clinic operation. Many practices have restricted services, especially those in an area of higher COVID-19 prevalence. However, the challenge of determining day-to-day operation may have been left to the provider in most cases.⁴ As many states in the United States continue to relax restrictions, total cases and the rate of positivity of COVID-19 have been sharply rising again, after months of decline,⁵ which suggests increased transmission of SARS-CoV-2 and potential resurgence of the high case burden on our health care system. Furthermore, a lack of a widely distributed vaccine or herd immunity suggests we will need to take many of the same precautions as in the first surge.⁶

In general, patients with cancer have been found to be at greater risk for adverse outcomes and mortality after COVID-19.⁷ Therefore, resource rationing is particularly concerning for patients with skin cancer, including melanoma, Merkel cell carcinoma, mycosis fungoides, and keratinocyte carcinoma. Triaging patients based on level of acuity, type of skin cancer, disease burden, host immunosuppression, and risk for progression must be carefully considered in this population.² Treatment and follow-up present additional challenges.

Guidelines provided by the National Comprehensive Cancer Network (NCCN) and the European Society for Medical Oncology (ESMO) elaborated on key considerations for the treatment of melanoma, keratinocyte carcinoma, and Merkel cell carcinoma during the COVID-19 pandemic.^8-10 Guidelines from the NCCN concentrated on clear divisions between disease stages to determine provider response. Guidelines for melanoma patients proposed by the ESMO assign tiers by value-based priority in various treatment settings, which offered flexibility to providers as the COVID-19 landscape continued to change. Recommendations from the NCCN and ESMO are summarized in Tables 1 to 5.

Tips for Performing Dermatologic Surgery

Careful consideration should be made to protect both the patient and staff during office-based excisional surgery during the COVID-19 pandemic. To minimize the risk of transmission of SARS-CoV-2, patients and staff should (1) be screened for symptoms of COVID-19 at least 48 hours prior to entering the office via telephone screening questions, and (2) follow proper hygiene and contact procedures once entering the office. Consider obtaining a nasal polymerase chain reaction swab or saliva test 48 hours prior to the procedure if the patient is undergoing a head and neck procedure or there is risk for transmission.

Guidelines from the ESMO recommended that all patients undergoing surgery or therapy should be swabbed for SARS-CoV-2 before each treatment.¹¹ Patients should wear a mask, remain 6-feet apart in the waiting room, and avoid touching objects until they enter the procedure room. Objects that the patient must touch, such as pens, should be cleaned immediately after such contact with either alcohol or soap and water for 20 seconds.

Office capacity should be reduced by allowing no more than 1 person to accompany the patient and ensuring the presence of only the minimum staff needed for the procedure. Staff who are deemed necessary should wear a mask continuously and gloves during patient contact.

Once in the procedure room, providers might be at elevated risk of contracting COVID-19 or transmitting SARS-CoV-2. A properly fitted N95 respirator and a face shield are recommended, especially for facial cases. N95 respirators can be reused by following the latest Centers for Disease Control and Prevention recommendations for reuse and decontamination techniques,¹³ which may include protecting the N95 respirator with a surgical mask and storing it in a paper bag when not in use. Consider testing asymptomatic patients in facial cases when they cannot wear a mask.

Steps should be taken to reduce in-person visits. Dissolving sutures can help avoid return visits. Follow-up visits and postprocedural questions should be managed by telehealth. However, patients with a high-risk underlying conditions (eg, posttransplantation, immunosuppressed) should continue to obtain regular skin checks because they are at higher risk for more aggressive malignancies, such as Merkel cell carcinoma.

Conclusion

The future trajectory of the COVID-19 pandemic is uncertain. Dermatologists should continue providing care for patients with skin cancer while mitigating the risk for COVID-19 infection and transmission of SARS-CoV-2. Guidelines provided by the NCCN and ESMO should help providers triage patients. Decisions should be made case by case, keeping in mind the availability of resources and practicing in compliance with local guidance.

Case Report

A 67-year-old Black woman presented with a long-standing history of pruritus and “scaly thick bumps” on the lower extremities. Upon further questioning, she reported a 30-year history of placing her feet by an electric space heater and daily baths in “very hot” water. A review of systems and medical history were unremarkable, and the patient was not on any medications. Initial physical examination of the lower extremities demonstrated lichenified plaques and scattered, firm, ulcerated nodules surrounded by mottled postinflammatory hyperpigmentation with sharp demarcation at the midcalf bilaterally (Figure 1).

Subsequently, the patient was shown to have multiple actinic keratoses and SCCs, both in situ and invasive, within the areas of EAI (Figure 2). The patient had no actinic keratoses or other cutaneous malignant neoplasms elsewhere on the skin. Management of actinic keratoses, SCC in situ, and invasive SCC on the lower extremities included numerous excisions, treatment with liquid nitrogen, and topical 5-fluorouracil under occlusion. The patient continues to be monitored frequently.

Comment

Presentation of EAI
Erythema ab igne is a cutaneous reaction resulting from prolonged exposure to an infrared heat source at temperatures insufficient to cause a burn (37 °F to 113 °F [2.78 °C to 45 °C]). Initially presenting as transient blanchable erythema, chronic heat exposure induces persistent areas of reticular erythema, often accompanied by hyperpigmentation, epidermal atrophy, and telangiectases.¹ Erythema ab igne is most commonly reported on the anterior shins, inner thighs, and back, and it is historically associated with open fires and coal stoves. More recently, other implicated causes include heating pads, laptop computers, heated furniture, and electric space heaters.^2,3 Erythema ab igne often is asymptomatic but can present with pruritus and a burning sensation. Treatment involves removal of the inciting heat source, which might allow resolution of early-stage lesions. Long-term exposure leads to permanent skin discoloration and on occasion predisposes patients to malignant transformation.³

Histopathology of EAI
Histologically, later stages of EAI can demonstrate focal hyperkeratosis with dyskeratosis and increased dermal elastosis, similar to actinic damage, with a predisposition to develop SCC.² Notably, early reports document various heat-induced carcinomas, including kangri-burn cancers among Kashmiris, kang thermal cancers in China, and kairo cancers in Japan.^2,4,5 More recent reports identify cutaneous carcinomas arising specifically in the setting of EAI, most commonly SCC³; Merkel cell carcinoma and cutaneous marginal zone lymphoma are less commonly reported malignancies.^6,7 Given the frequency of malignant transformation within sites of thermal exposure, chronic heat exposure may share a common pathophysiology with SCC and other neoplasms, including Merkel cell carcinoma and cutaneous marginal zone lymphoma.

SCC in Black Individuals
Squamous cell carcinoma is the most common skin cancer in Black individuals, with a notably higher incidence in high-risk subpopulations (immunosuppressed patients). Unlike White individuals, SCCs frequently occur in non–sun-exposed areas in Black individuals and are associated with unique risk factors, such as human papillomavirus, as demonstrated in Black transplant patients.⁸ A retrospective study examining the characteristics of SCC on the legs of Black individuals documented atypical hyperkeratotic neoplasms surrounded by abnormal pigmentation and mottling of surrounding skin.⁹ Morphologic skin changes could be the result of chronic thermal damage: Numerous patients reported a history of leg warming from an open heat source. Other patients had an actual diagnosis of EAI. The predilection for less-exposed skin suggests UV radiation (UVR) might be a less important predisposing risk factor for this racial group, and the increased mortality associated with SCC in Black individuals might represent a more aggressive nature to this subset of SCCs.⁹ Furthermore, infrared radiation (IRR), such as fires and coal stoves, might have the potential to stimulate skin changes similar to those associated with UVR and ultimately malignant changes.

Infrared Radiation
Compared to UVR, little is known about the biological effects of IRR (wavelength, 760 nm to 1 mm), to which human skin is constantly exposed from natural and artificial light sources. Early studies have demonstrated the carcinogenic potential of IRR, observing an augmentation of UVR-induced tumorigenesis in the presence of heat. More recently, IRR was observed to stimulate increased collagenase production from dermal fibroblasts and influence pathways (extracellular signal-related kinases 1/2 and p38 mitogen-activated protein kinases) in a similar fashion to UVB and UVA.^10,11 Therefore, IRR might be capable of eliciting molecular responses comparable to those caused by UVR.

Conclusion

Although SCC in association with EAI is uncommon, historical reports of thermal cancers and scientific observations of IRR-induced biological and molecular effects support EAI as a predisposing risk factor for SCC and the important need for close monitoring by physicians. Studies are needed to further elucidate the pathologic effects of IRR, with more promotion of caution relating to thermal exposure.

Case Report

A 67-year-old Black woman presented with a long-standing history of pruritus and “scaly thick bumps” on the lower extremities. Upon further questioning, she reported a 30-year history of placing her feet by an electric space heater and daily baths in “very hot” water. A review of systems and medical history were unremarkable, and the patient was not on any medications. Initial physical examination of the lower extremities demonstrated lichenified plaques and scattered, firm, ulcerated nodules surrounded by mottled postinflammatory hyperpigmentation with sharp demarcation at the midcalf bilaterally (Figure 1).

Subsequently, the patient was shown to have multiple actinic keratoses and SCCs, both in situ and invasive, within the areas of EAI (Figure 2). The patient had no actinic keratoses or other cutaneous malignant neoplasms elsewhere on the skin. Management of actinic keratoses, SCC in situ, and invasive SCC on the lower extremities included numerous excisions, treatment with liquid nitrogen, and topical 5-fluorouracil under occlusion. The patient continues to be monitored frequently.

Comment

Presentation of EAI
Erythema ab igne is a cutaneous reaction resulting from prolonged exposure to an infrared heat source at temperatures insufficient to cause a burn (37 °F to 113 °F [2.78 °C to 45 °C]). Initially presenting as transient blanchable erythema, chronic heat exposure induces persistent areas of reticular erythema, often accompanied by hyperpigmentation, epidermal atrophy, and telangiectases.¹ Erythema ab igne is most commonly reported on the anterior shins, inner thighs, and back, and it is historically associated with open fires and coal stoves. More recently, other implicated causes include heating pads, laptop computers, heated furniture, and electric space heaters.^2,3 Erythema ab igne often is asymptomatic but can present with pruritus and a burning sensation. Treatment involves removal of the inciting heat source, which might allow resolution of early-stage lesions. Long-term exposure leads to permanent skin discoloration and on occasion predisposes patients to malignant transformation.³

Histopathology of EAI
Histologically, later stages of EAI can demonstrate focal hyperkeratosis with dyskeratosis and increased dermal elastosis, similar to actinic damage, with a predisposition to develop SCC.² Notably, early reports document various heat-induced carcinomas, including kangri-burn cancers among Kashmiris, kang thermal cancers in China, and kairo cancers in Japan.^2,4,5 More recent reports identify cutaneous carcinomas arising specifically in the setting of EAI, most commonly SCC³; Merkel cell carcinoma and cutaneous marginal zone lymphoma are less commonly reported malignancies.^6,7 Given the frequency of malignant transformation within sites of thermal exposure, chronic heat exposure may share a common pathophysiology with SCC and other neoplasms, including Merkel cell carcinoma and cutaneous marginal zone lymphoma.

SCC in Black Individuals
Squamous cell carcinoma is the most common skin cancer in Black individuals, with a notably higher incidence in high-risk subpopulations (immunosuppressed patients). Unlike White individuals, SCCs frequently occur in non–sun-exposed areas in Black individuals and are associated with unique risk factors, such as human papillomavirus, as demonstrated in Black transplant patients.⁸ A retrospective study examining the characteristics of SCC on the legs of Black individuals documented atypical hyperkeratotic neoplasms surrounded by abnormal pigmentation and mottling of surrounding skin.⁹ Morphologic skin changes could be the result of chronic thermal damage: Numerous patients reported a history of leg warming from an open heat source. Other patients had an actual diagnosis of EAI. The predilection for less-exposed skin suggests UV radiation (UVR) might be a less important predisposing risk factor for this racial group, and the increased mortality associated with SCC in Black individuals might represent a more aggressive nature to this subset of SCCs.⁹ Furthermore, infrared radiation (IRR), such as fires and coal stoves, might have the potential to stimulate skin changes similar to those associated with UVR and ultimately malignant changes.

Infrared Radiation
Compared to UVR, little is known about the biological effects of IRR (wavelength, 760 nm to 1 mm), to which human skin is constantly exposed from natural and artificial light sources. Early studies have demonstrated the carcinogenic potential of IRR, observing an augmentation of UVR-induced tumorigenesis in the presence of heat. More recently, IRR was observed to stimulate increased collagenase production from dermal fibroblasts and influence pathways (extracellular signal-related kinases 1/2 and p38 mitogen-activated protein kinases) in a similar fashion to UVB and UVA.^10,11 Therefore, IRR might be capable of eliciting molecular responses comparable to those caused by UVR.

Conclusion

Although SCC in association with EAI is uncommon, historical reports of thermal cancers and scientific observations of IRR-induced biological and molecular effects support EAI as a predisposing risk factor for SCC and the important need for close monitoring by physicians. Studies are needed to further elucidate the pathologic effects of IRR, with more promotion of caution relating to thermal exposure.

Case Report

A 67-year-old Black woman presented with a long-standing history of pruritus and “scaly thick bumps” on the lower extremities. Upon further questioning, she reported a 30-year history of placing her feet by an electric space heater and daily baths in “very hot” water. A review of systems and medical history were unremarkable, and the patient was not on any medications. Initial physical examination of the lower extremities demonstrated lichenified plaques and scattered, firm, ulcerated nodules surrounded by mottled postinflammatory hyperpigmentation with sharp demarcation at the midcalf bilaterally (Figure 1).

Subsequently, the patient was shown to have multiple actinic keratoses and SCCs, both in situ and invasive, within the areas of EAI (Figure 2). The patient had no actinic keratoses or other cutaneous malignant neoplasms elsewhere on the skin. Management of actinic keratoses, SCC in situ, and invasive SCC on the lower extremities included numerous excisions, treatment with liquid nitrogen, and topical 5-fluorouracil under occlusion. The patient continues to be monitored frequently.

Comment

Presentation of EAI
Erythema ab igne is a cutaneous reaction resulting from prolonged exposure to an infrared heat source at temperatures insufficient to cause a burn (37 °F to 113 °F [2.78 °C to 45 °C]). Initially presenting as transient blanchable erythema, chronic heat exposure induces persistent areas of reticular erythema, often accompanied by hyperpigmentation, epidermal atrophy, and telangiectases.¹ Erythema ab igne is most commonly reported on the anterior shins, inner thighs, and back, and it is historically associated with open fires and coal stoves. More recently, other implicated causes include heating pads, laptop computers, heated furniture, and electric space heaters.^2,3 Erythema ab igne often is asymptomatic but can present with pruritus and a burning sensation. Treatment involves removal of the inciting heat source, which might allow resolution of early-stage lesions. Long-term exposure leads to permanent skin discoloration and on occasion predisposes patients to malignant transformation.³

Histopathology of EAI
Histologically, later stages of EAI can demonstrate focal hyperkeratosis with dyskeratosis and increased dermal elastosis, similar to actinic damage, with a predisposition to develop SCC.² Notably, early reports document various heat-induced carcinomas, including kangri-burn cancers among Kashmiris, kang thermal cancers in China, and kairo cancers in Japan.^2,4,5 More recent reports identify cutaneous carcinomas arising specifically in the setting of EAI, most commonly SCC³; Merkel cell carcinoma and cutaneous marginal zone lymphoma are less commonly reported malignancies.^6,7 Given the frequency of malignant transformation within sites of thermal exposure, chronic heat exposure may share a common pathophysiology with SCC and other neoplasms, including Merkel cell carcinoma and cutaneous marginal zone lymphoma.

SCC in Black Individuals
Squamous cell carcinoma is the most common skin cancer in Black individuals, with a notably higher incidence in high-risk subpopulations (immunosuppressed patients). Unlike White individuals, SCCs frequently occur in non–sun-exposed areas in Black individuals and are associated with unique risk factors, such as human papillomavirus, as demonstrated in Black transplant patients.⁸ A retrospective study examining the characteristics of SCC on the legs of Black individuals documented atypical hyperkeratotic neoplasms surrounded by abnormal pigmentation and mottling of surrounding skin.⁹ Morphologic skin changes could be the result of chronic thermal damage: Numerous patients reported a history of leg warming from an open heat source. Other patients had an actual diagnosis of EAI. The predilection for less-exposed skin suggests UV radiation (UVR) might be a less important predisposing risk factor for this racial group, and the increased mortality associated with SCC in Black individuals might represent a more aggressive nature to this subset of SCCs.⁹ Furthermore, infrared radiation (IRR), such as fires and coal stoves, might have the potential to stimulate skin changes similar to those associated with UVR and ultimately malignant changes.

Infrared Radiation
Compared to UVR, little is known about the biological effects of IRR (wavelength, 760 nm to 1 mm), to which human skin is constantly exposed from natural and artificial light sources. Early studies have demonstrated the carcinogenic potential of IRR, observing an augmentation of UVR-induced tumorigenesis in the presence of heat. More recently, IRR was observed to stimulate increased collagenase production from dermal fibroblasts and influence pathways (extracellular signal-related kinases 1/2 and p38 mitogen-activated protein kinases) in a similar fashion to UVB and UVA.^10,11 Therefore, IRR might be capable of eliciting molecular responses comparable to those caused by UVR.

Conclusion

Although SCC in association with EAI is uncommon, historical reports of thermal cancers and scientific observations of IRR-induced biological and molecular effects support EAI as a predisposing risk factor for SCC and the important need for close monitoring by physicians. Studies are needed to further elucidate the pathologic effects of IRR, with more promotion of caution relating to thermal exposure.