Nonmelanoma Skin Cancer

Cutaneous metastasis of internal malignancy is a relatively uncommon phenomenon, with an overall incidence of 5.3% in cancer patients.¹ Cutaneous involvement typically occurs late in the course of disease but can occasionally be the first extranodal sign of metastatic disease. Breast cancer has the highest rate of cutaneous metastasis, most often involving the chest wall¹; however, cutaneous metastasis to the acral sites is exceedingly rare. The hand is the site of 0.1% of all metastatic lesions, with only 10% of these being cutaneous lesions and the remaining 90% being osseous metastases.² Herein, we report a case of multiple cutaneous metastases to acral sites involving the palmar and plantar surfaces of the hands and feet.

Case Report

A 54-year-old black woman with a history of stage IV carcinoma of the breast was admitted to the university medical center with exquisitely painful cutaneous nodules on the hands and feet of 5 weeks’ duration that had started to cause difficulty with walking and daily activities. The patient reported that the breast carcinoma had initially been diagnosed in Nigeria 2 years prior, but she did not receive treatment until moving to the United States. She received a total of 4 cycles of chemotherapy with paclitaxel and bevacizumab, which was discontinued 6 weeks prior to admission due to pain in the lower extremities that was thought to be secondary to neuropathy. One week after discontinuation of chemotherapy, the patient reported increasing pain in the extremities and new-onset painful nodules on the hands and feet. Treatment with gabapentin as well as several courses of antibiotics failed to improve the condition.

She was admitted for symptomatic pain control and a dermatology consultation. Physical examination revealed multiple firm, tender, subcutaneous nodules on the volar surfaces of the soles, toes, palms, and fingertips (Figure 1). A nodule also was noted on the scalp. A punch biopsy of a nodule on the right fourth finger revealed a dermal carcinoma (Figure 2). On immunohistochemistry, the tumor stained positive for cytokeratin 5/6, cytokeratin 7, and gross cystic disease fluid protein 15. It did not demonstrate connection to the epidermis or adnexal structures. Although the tumor did not express estrogen or progesterone receptors, the findings were compatible with metastasis from the patient’s primary breast carcinoma with poor differentiation. A biopsy of the primary breast carcinoma was not available for review from Nigeria.

Comment

The majority of cases reporting acral cutaneous metastasis from internal malignancies are unilateral, involving only one extremity. Several hypotheses have been provided, including spread from localized trauma, which causes disruption of blood vessels and consequent extravasation and localization of tumor cells into the extravascular space.³ The distal extremities are particularly vulnerable to trauma, making this hypothesis plausible.

Considering the overall rarity of metastases to acral sites, it is interesting that our patient developed multiple distal nodules on both the hands and feet. The rapid onset of cutaneous nodules shortly after a course of chemotherapy led the team to consider the physiologic effects of paclitaxel and bevacizumab in the etiology of the acral cutaneous metastases. Karamouzis et al³ described a similar case of multiple cutaneous metastases with a bilateral acral distribution. This case also was associated with chemotherapy in the treatment of breast cancer. The authors proposed hand-foot syndrome, a chemotherapy-related eruption localized to acral skin, as a possible mechanism for hematogenous spread of malignant cells.³ The pathogenesis of hand-foot syndrome is not well understood, but the unique anatomy and physiology of acral skin including temperature gradients, rapidly dividing epidermal cells, absence of hair follicles and sebaceous glands, wide dermal papillae, and exposure to high pressures from carrying body weight and repetitive minor trauma may contribute to the localization of signs and symptoms.^3,4 Our case supports a chemotherapy-related etiology of acral cutaneous metastasis of a primary breast cancer; however, our patient did not have apparent signs or symptoms of hand-foot syndrome during the course of treatment. We propose that effects of bevacizumab on acral skin may have contributed to the development of our patient’s metastatic pattern.

Bevacizumab, a monoclonal antibody to vascular endothelial growth factor A, has well-known vascular side effects. Unlike the inhibition of vascular endothelial growth factor A provided by the receptor tyrosine kinase inhibitors sorafenib and sunitinib, bevacizumab typically is not associated with hand-foot syndrome.⁵ However, several cases have been reported with chemotherapy-associated palmoplantar eruptions that resolved after withholding bevacizumab while continuing other chemotherapeutic agents, suggesting that bevacizumab-induced changes in acral skin contributed to the eruption.⁶ Specific factors that could contribute to acral metastasis in patients taking bevacizumab are endothelial dysfunction and capillary rarefaction of the acral skin, as well as hemorrhage, decreased wound healing, and changes in vascular permeability.^5,7

We present a rare case of acral cutaneous metastasis associated with bevacizumab, one of few reported cases associated with a taxane chemotherapeutic agent.³ More cases need to be identified and reported to establish a causative association, if indeed existent, between acral cutaneous metastasis of breast carcinoma and the use of bevacizumab as well as other chemotherapeutic drugs.

Cutaneous metastasis of internal malignancy is a relatively uncommon phenomenon, with an overall incidence of 5.3% in cancer patients.¹ Cutaneous involvement typically occurs late in the course of disease but can occasionally be the first extranodal sign of metastatic disease. Breast cancer has the highest rate of cutaneous metastasis, most often involving the chest wall¹; however, cutaneous metastasis to the acral sites is exceedingly rare. The hand is the site of 0.1% of all metastatic lesions, with only 10% of these being cutaneous lesions and the remaining 90% being osseous metastases.² Herein, we report a case of multiple cutaneous metastases to acral sites involving the palmar and plantar surfaces of the hands and feet.

Case Report

A 54-year-old black woman with a history of stage IV carcinoma of the breast was admitted to the university medical center with exquisitely painful cutaneous nodules on the hands and feet of 5 weeks’ duration that had started to cause difficulty with walking and daily activities. The patient reported that the breast carcinoma had initially been diagnosed in Nigeria 2 years prior, but she did not receive treatment until moving to the United States. She received a total of 4 cycles of chemotherapy with paclitaxel and bevacizumab, which was discontinued 6 weeks prior to admission due to pain in the lower extremities that was thought to be secondary to neuropathy. One week after discontinuation of chemotherapy, the patient reported increasing pain in the extremities and new-onset painful nodules on the hands and feet. Treatment with gabapentin as well as several courses of antibiotics failed to improve the condition.

She was admitted for symptomatic pain control and a dermatology consultation. Physical examination revealed multiple firm, tender, subcutaneous nodules on the volar surfaces of the soles, toes, palms, and fingertips (Figure 1). A nodule also was noted on the scalp. A punch biopsy of a nodule on the right fourth finger revealed a dermal carcinoma (Figure 2). On immunohistochemistry, the tumor stained positive for cytokeratin 5/6, cytokeratin 7, and gross cystic disease fluid protein 15. It did not demonstrate connection to the epidermis or adnexal structures. Although the tumor did not express estrogen or progesterone receptors, the findings were compatible with metastasis from the patient’s primary breast carcinoma with poor differentiation. A biopsy of the primary breast carcinoma was not available for review from Nigeria.

Comment

The majority of cases reporting acral cutaneous metastasis from internal malignancies are unilateral, involving only one extremity. Several hypotheses have been provided, including spread from localized trauma, which causes disruption of blood vessels and consequent extravasation and localization of tumor cells into the extravascular space.³ The distal extremities are particularly vulnerable to trauma, making this hypothesis plausible.

Considering the overall rarity of metastases to acral sites, it is interesting that our patient developed multiple distal nodules on both the hands and feet. The rapid onset of cutaneous nodules shortly after a course of chemotherapy led the team to consider the physiologic effects of paclitaxel and bevacizumab in the etiology of the acral cutaneous metastases. Karamouzis et al³ described a similar case of multiple cutaneous metastases with a bilateral acral distribution. This case also was associated with chemotherapy in the treatment of breast cancer. The authors proposed hand-foot syndrome, a chemotherapy-related eruption localized to acral skin, as a possible mechanism for hematogenous spread of malignant cells.³ The pathogenesis of hand-foot syndrome is not well understood, but the unique anatomy and physiology of acral skin including temperature gradients, rapidly dividing epidermal cells, absence of hair follicles and sebaceous glands, wide dermal papillae, and exposure to high pressures from carrying body weight and repetitive minor trauma may contribute to the localization of signs and symptoms.^3,4 Our case supports a chemotherapy-related etiology of acral cutaneous metastasis of a primary breast cancer; however, our patient did not have apparent signs or symptoms of hand-foot syndrome during the course of treatment. We propose that effects of bevacizumab on acral skin may have contributed to the development of our patient’s metastatic pattern.

Bevacizumab, a monoclonal antibody to vascular endothelial growth factor A, has well-known vascular side effects. Unlike the inhibition of vascular endothelial growth factor A provided by the receptor tyrosine kinase inhibitors sorafenib and sunitinib, bevacizumab typically is not associated with hand-foot syndrome.⁵ However, several cases have been reported with chemotherapy-associated palmoplantar eruptions that resolved after withholding bevacizumab while continuing other chemotherapeutic agents, suggesting that bevacizumab-induced changes in acral skin contributed to the eruption.⁶ Specific factors that could contribute to acral metastasis in patients taking bevacizumab are endothelial dysfunction and capillary rarefaction of the acral skin, as well as hemorrhage, decreased wound healing, and changes in vascular permeability.^5,7

We present a rare case of acral cutaneous metastasis associated with bevacizumab, one of few reported cases associated with a taxane chemotherapeutic agent.³ More cases need to be identified and reported to establish a causative association, if indeed existent, between acral cutaneous metastasis of breast carcinoma and the use of bevacizumab as well as other chemotherapeutic drugs.

Cutaneous metastasis of internal malignancy is a relatively uncommon phenomenon, with an overall incidence of 5.3% in cancer patients.¹ Cutaneous involvement typically occurs late in the course of disease but can occasionally be the first extranodal sign of metastatic disease. Breast cancer has the highest rate of cutaneous metastasis, most often involving the chest wall¹; however, cutaneous metastasis to the acral sites is exceedingly rare. The hand is the site of 0.1% of all metastatic lesions, with only 10% of these being cutaneous lesions and the remaining 90% being osseous metastases.² Herein, we report a case of multiple cutaneous metastases to acral sites involving the palmar and plantar surfaces of the hands and feet.

Case Report

A 54-year-old black woman with a history of stage IV carcinoma of the breast was admitted to the university medical center with exquisitely painful cutaneous nodules on the hands and feet of 5 weeks’ duration that had started to cause difficulty with walking and daily activities. The patient reported that the breast carcinoma had initially been diagnosed in Nigeria 2 years prior, but she did not receive treatment until moving to the United States. She received a total of 4 cycles of chemotherapy with paclitaxel and bevacizumab, which was discontinued 6 weeks prior to admission due to pain in the lower extremities that was thought to be secondary to neuropathy. One week after discontinuation of chemotherapy, the patient reported increasing pain in the extremities and new-onset painful nodules on the hands and feet. Treatment with gabapentin as well as several courses of antibiotics failed to improve the condition.

She was admitted for symptomatic pain control and a dermatology consultation. Physical examination revealed multiple firm, tender, subcutaneous nodules on the volar surfaces of the soles, toes, palms, and fingertips (Figure 1). A nodule also was noted on the scalp. A punch biopsy of a nodule on the right fourth finger revealed a dermal carcinoma (Figure 2). On immunohistochemistry, the tumor stained positive for cytokeratin 5/6, cytokeratin 7, and gross cystic disease fluid protein 15. It did not demonstrate connection to the epidermis or adnexal structures. Although the tumor did not express estrogen or progesterone receptors, the findings were compatible with metastasis from the patient’s primary breast carcinoma with poor differentiation. A biopsy of the primary breast carcinoma was not available for review from Nigeria.

Comment

The majority of cases reporting acral cutaneous metastasis from internal malignancies are unilateral, involving only one extremity. Several hypotheses have been provided, including spread from localized trauma, which causes disruption of blood vessels and consequent extravasation and localization of tumor cells into the extravascular space.³ The distal extremities are particularly vulnerable to trauma, making this hypothesis plausible.

Considering the overall rarity of metastases to acral sites, it is interesting that our patient developed multiple distal nodules on both the hands and feet. The rapid onset of cutaneous nodules shortly after a course of chemotherapy led the team to consider the physiologic effects of paclitaxel and bevacizumab in the etiology of the acral cutaneous metastases. Karamouzis et al³ described a similar case of multiple cutaneous metastases with a bilateral acral distribution. This case also was associated with chemotherapy in the treatment of breast cancer. The authors proposed hand-foot syndrome, a chemotherapy-related eruption localized to acral skin, as a possible mechanism for hematogenous spread of malignant cells.³ The pathogenesis of hand-foot syndrome is not well understood, but the unique anatomy and physiology of acral skin including temperature gradients, rapidly dividing epidermal cells, absence of hair follicles and sebaceous glands, wide dermal papillae, and exposure to high pressures from carrying body weight and repetitive minor trauma may contribute to the localization of signs and symptoms.^3,4 Our case supports a chemotherapy-related etiology of acral cutaneous metastasis of a primary breast cancer; however, our patient did not have apparent signs or symptoms of hand-foot syndrome during the course of treatment. We propose that effects of bevacizumab on acral skin may have contributed to the development of our patient’s metastatic pattern.

Bevacizumab, a monoclonal antibody to vascular endothelial growth factor A, has well-known vascular side effects. Unlike the inhibition of vascular endothelial growth factor A provided by the receptor tyrosine kinase inhibitors sorafenib and sunitinib, bevacizumab typically is not associated with hand-foot syndrome.⁵ However, several cases have been reported with chemotherapy-associated palmoplantar eruptions that resolved after withholding bevacizumab while continuing other chemotherapeutic agents, suggesting that bevacizumab-induced changes in acral skin contributed to the eruption.⁶ Specific factors that could contribute to acral metastasis in patients taking bevacizumab are endothelial dysfunction and capillary rarefaction of the acral skin, as well as hemorrhage, decreased wound healing, and changes in vascular permeability.^5,7

We present a rare case of acral cutaneous metastasis associated with bevacizumab, one of few reported cases associated with a taxane chemotherapeutic agent.³ More cases need to be identified and reported to establish a causative association, if indeed existent, between acral cutaneous metastasis of breast carcinoma and the use of bevacizumab as well as other chemotherapeutic drugs.

Signs of efficacy of anti-cancer therapies may be only skin deep, results of a retrospective review indicate.

Cutaneous toxicities such as vitiligo, rash, alopecia, and nail toxicities may be early signs of efficacy of targeted therapies, immunotherapy, or cytotoxic chemotherapy, according to Alexandra K. Rzepecki, of the University of Michigan, and her coauthors from Albert Einstein Medical College in the Bronx, New York.

“Because cutaneous toxicities are a clinically visible parameter, they may alert clinicians to the possibility of treatment success or failure in a rapid, cost-effective, and noninvasive manner,” they wrote. The report is in the Journal of the American Academy of Dermatology.

The investigators reviewed the medical literature for clinical studies of three major classes of anti-cancer therapies that included data on associations between cutaneous toxicities and clinical outcomes such progression-free survival (PFS) overall survival (OS).

The drug classes and their associations with cutaneous toxicities and clinical outcomes were as follows:

• Targeted therapies, including tyrosine kinase inhibitors targeting the epidermal growth factor receptor (EGFR) such as cetuximab (Erbitux) and erlotinib (Tarceva), and multikinase targeted agents such as sorafenib (Nexavar) and sunitinib (Sutent). Toxicities associated with clinical benefit from EGFR inhibitors include rash, xerosis, leukocytoclastic vasculitis, paronychia, and pruritus, whereas skin toxicities associated with the multikinase inhibitors trended toward the hand-foot syndrome and hand-foot skin reaction.
• Immunotherapies included blockers of cytotoxic T-lymphocyte associated protein 4 (CTLA4) such as ipilimumab (Yervoy) and inhibitors of programmed death 1 protein (PD-1) and its ligand 1 (PD-L1) such as nivolumab (Opdivo), pembrolizumab (Keytruda), and atezolizumab (Tecentriq). In studies of pembrolizumab for various malignancies, rash or vitiligo was an independent prognostic factor for longer OS, a higher proportion of objective responses, and longer PFS. Similar associations were seen with nivolumab, with the additional association of hair repigmentation among patients with non–small-cell lung cancer being associated with stable disease responses or better. Among patients with melanoma treated with ipilimumab, hair depigmentation correlated with durable responses.
• Cytotoxic chemotherapy agents included the anthracycline doxorubicin, taxanes such as paclitaxel and docetaxel, platinum agents (cisplatin and carboplatin), and fluoropyrimidines such as capecitabine. Patients treated for various cancers with doxorubicin who had alopecia were significantly more likely to have clinical remissions than were patients who did not lose their hair, and patients treated with this agent who developed hand-foot syndrome had significantly longer PFS. For patients treated with docetaxel, severity of nail changes and/or development of nail alterations were associated with both improved OS and PFS. Patients treated with the combination of paclitaxel and a platinum agent who developed grade 2 or greater alopecia up to cycle 3 had significantly longer OS than did patients who had hair loss later in the course of therapy. Patients treated with capecitabine who developed had hand-foot skin reactions had improved progression-free and disease-free survival.

“Although further studies are needed to better evaluate these promising associations, vigilant monitoring of cutaneous toxicities should be a priority, as their development may indicate a favorable response to treatment. Dermatologists have a unique opportunity to collaborate with oncologists to help identify and manage these toxicities, thereby allowing patients to receive life-prolonging anticancer therapy while minimizing dose reduction or interruption of their treatment,” the authors wrote.

They reported no study funding source and no conflicts of interest.

SOURCE: Rzepecki A, et al. J Am Acad Dermatol. 2018;79:545-555.

Signs of efficacy of anti-cancer therapies may be only skin deep, results of a retrospective review indicate.

Cutaneous toxicities such as vitiligo, rash, alopecia, and nail toxicities may be early signs of efficacy of targeted therapies, immunotherapy, or cytotoxic chemotherapy, according to Alexandra K. Rzepecki, of the University of Michigan, and her coauthors from Albert Einstein Medical College in the Bronx, New York.

“Because cutaneous toxicities are a clinically visible parameter, they may alert clinicians to the possibility of treatment success or failure in a rapid, cost-effective, and noninvasive manner,” they wrote. The report is in the Journal of the American Academy of Dermatology.

The investigators reviewed the medical literature for clinical studies of three major classes of anti-cancer therapies that included data on associations between cutaneous toxicities and clinical outcomes such progression-free survival (PFS) overall survival (OS).

The drug classes and their associations with cutaneous toxicities and clinical outcomes were as follows:

• Targeted therapies, including tyrosine kinase inhibitors targeting the epidermal growth factor receptor (EGFR) such as cetuximab (Erbitux) and erlotinib (Tarceva), and multikinase targeted agents such as sorafenib (Nexavar) and sunitinib (Sutent). Toxicities associated with clinical benefit from EGFR inhibitors include rash, xerosis, leukocytoclastic vasculitis, paronychia, and pruritus, whereas skin toxicities associated with the multikinase inhibitors trended toward the hand-foot syndrome and hand-foot skin reaction.
• Immunotherapies included blockers of cytotoxic T-lymphocyte associated protein 4 (CTLA4) such as ipilimumab (Yervoy) and inhibitors of programmed death 1 protein (PD-1) and its ligand 1 (PD-L1) such as nivolumab (Opdivo), pembrolizumab (Keytruda), and atezolizumab (Tecentriq). In studies of pembrolizumab for various malignancies, rash or vitiligo was an independent prognostic factor for longer OS, a higher proportion of objective responses, and longer PFS. Similar associations were seen with nivolumab, with the additional association of hair repigmentation among patients with non–small-cell lung cancer being associated with stable disease responses or better. Among patients with melanoma treated with ipilimumab, hair depigmentation correlated with durable responses.
• Cytotoxic chemotherapy agents included the anthracycline doxorubicin, taxanes such as paclitaxel and docetaxel, platinum agents (cisplatin and carboplatin), and fluoropyrimidines such as capecitabine. Patients treated for various cancers with doxorubicin who had alopecia were significantly more likely to have clinical remissions than were patients who did not lose their hair, and patients treated with this agent who developed hand-foot syndrome had significantly longer PFS. For patients treated with docetaxel, severity of nail changes and/or development of nail alterations were associated with both improved OS and PFS. Patients treated with the combination of paclitaxel and a platinum agent who developed grade 2 or greater alopecia up to cycle 3 had significantly longer OS than did patients who had hair loss later in the course of therapy. Patients treated with capecitabine who developed had hand-foot skin reactions had improved progression-free and disease-free survival.

“Although further studies are needed to better evaluate these promising associations, vigilant monitoring of cutaneous toxicities should be a priority, as their development may indicate a favorable response to treatment. Dermatologists have a unique opportunity to collaborate with oncologists to help identify and manage these toxicities, thereby allowing patients to receive life-prolonging anticancer therapy while minimizing dose reduction or interruption of their treatment,” the authors wrote.

They reported no study funding source and no conflicts of interest.

SOURCE: Rzepecki A, et al. J Am Acad Dermatol. 2018;79:545-555.

Signs of efficacy of anti-cancer therapies may be only skin deep, results of a retrospective review indicate.

Cutaneous toxicities such as vitiligo, rash, alopecia, and nail toxicities may be early signs of efficacy of targeted therapies, immunotherapy, or cytotoxic chemotherapy, according to Alexandra K. Rzepecki, of the University of Michigan, and her coauthors from Albert Einstein Medical College in the Bronx, New York.

“Because cutaneous toxicities are a clinically visible parameter, they may alert clinicians to the possibility of treatment success or failure in a rapid, cost-effective, and noninvasive manner,” they wrote. The report is in the Journal of the American Academy of Dermatology.

The investigators reviewed the medical literature for clinical studies of three major classes of anti-cancer therapies that included data on associations between cutaneous toxicities and clinical outcomes such progression-free survival (PFS) overall survival (OS).

The drug classes and their associations with cutaneous toxicities and clinical outcomes were as follows:

• Targeted therapies, including tyrosine kinase inhibitors targeting the epidermal growth factor receptor (EGFR) such as cetuximab (Erbitux) and erlotinib (Tarceva), and multikinase targeted agents such as sorafenib (Nexavar) and sunitinib (Sutent). Toxicities associated with clinical benefit from EGFR inhibitors include rash, xerosis, leukocytoclastic vasculitis, paronychia, and pruritus, whereas skin toxicities associated with the multikinase inhibitors trended toward the hand-foot syndrome and hand-foot skin reaction.
• Immunotherapies included blockers of cytotoxic T-lymphocyte associated protein 4 (CTLA4) such as ipilimumab (Yervoy) and inhibitors of programmed death 1 protein (PD-1) and its ligand 1 (PD-L1) such as nivolumab (Opdivo), pembrolizumab (Keytruda), and atezolizumab (Tecentriq). In studies of pembrolizumab for various malignancies, rash or vitiligo was an independent prognostic factor for longer OS, a higher proportion of objective responses, and longer PFS. Similar associations were seen with nivolumab, with the additional association of hair repigmentation among patients with non–small-cell lung cancer being associated with stable disease responses or better. Among patients with melanoma treated with ipilimumab, hair depigmentation correlated with durable responses.
• Cytotoxic chemotherapy agents included the anthracycline doxorubicin, taxanes such as paclitaxel and docetaxel, platinum agents (cisplatin and carboplatin), and fluoropyrimidines such as capecitabine. Patients treated for various cancers with doxorubicin who had alopecia were significantly more likely to have clinical remissions than were patients who did not lose their hair, and patients treated with this agent who developed hand-foot syndrome had significantly longer PFS. For patients treated with docetaxel, severity of nail changes and/or development of nail alterations were associated with both improved OS and PFS. Patients treated with the combination of paclitaxel and a platinum agent who developed grade 2 or greater alopecia up to cycle 3 had significantly longer OS than did patients who had hair loss later in the course of therapy. Patients treated with capecitabine who developed had hand-foot skin reactions had improved progression-free and disease-free survival.

“Although further studies are needed to better evaluate these promising associations, vigilant monitoring of cutaneous toxicities should be a priority, as their development may indicate a favorable response to treatment. Dermatologists have a unique opportunity to collaborate with oncologists to help identify and manage these toxicities, thereby allowing patients to receive life-prolonging anticancer therapy while minimizing dose reduction or interruption of their treatment,” the authors wrote.

They reported no study funding source and no conflicts of interest.

SOURCE: Rzepecki A, et al. J Am Acad Dermatol. 2018;79:545-555.

CHICAGO – The future looks bright for reflectance confocal microscopy (RCM) as a tie breaker to decide whether skin lesions that are equivocal on dermoscopy warrant biopsy to rule out malignancy, Ann M. John, MD, asserted at the annual meeting of the American College of Mohs Surgery.

“With the advent of dermoscopy, dermatologists were able to elucidate both benign and malignant patterns to help further guide their decision to biopsy or not. This increased diagnostic accuracy of suspicious lesions by 30%, while reducing the benign to malignant ratio of biopsies performed from 18:1 to 4:1. However, there are still lesions that are equivocal on dermoscopy, as we all know, and for this, there’s reflectance confocal microscopy,” observed Dr. John, of Robert Wood Johnson Medical School, New Brunswick, N.J.

RCM is a device technology that’s been cleared by the Food and Drug Administration since 2008 for the imaging of clinically suspicious lesions. It employs laser scanning to assess the light-scattering properties of cells in the epidermis and dermis, generating images with resolution comparable to histology.

RCM took a back seat initially while American dermatologists were gradually coming to embrace dermoscopy, which their European colleagues had done years earlier. Now, with the availability of handheld RCM for use in the dermatology clinic, expect RCM to assume a growing role in daily practice.

To illustrate the power of RCM as a diagnostic aid, she presented a single-center retrospective study of 1,189 clinically suspicious skin lesions that were equivocal on dermoscopy and then assessed using RCM with 1 year of subsequent patient follow-up. Overall, 155 lesions were deemed positive for cancer or atypia by RCM, while 1,034 were determined to be benign. Of those 155, 46 lesions were considered false positives because of their benign appearance on histologic inspection of the biopsy sample. Only 2 of the 1,034 lesions identified as negative by RCM proved to be false negatives on the basis of clinical changes within 1 year.

The overall sensitivity and specificity of RCM was 98.2% and 99.8%, respectively, with a positive predictive value of 70.3% and a negative predictive value of 99.8%.

The entire RCM procedure takes a skilled technician 15-20 minutes per lesion. As a practical matter, other investigators have estimated that RCM results in a cost savings of about $308,000 per million health plan members per year by reducing the need for biopsies (Dermatol Clin. 2016 Oct;34[4]:367-75).

In addition to evaluating clinically suspicious lesions, other situations in which RCM offers practical value include its use directly before the first cut during Mohs surgery in order to determine the margins of atypia; ex vivo imaging of Mohs margins, which has been shown to be comparable with frozen sections in accuracy but takes only one-third of the time; and imaging of biopsied lesions in order to determine the diagnosis relatively quickly, Dr. John noted.

She reported having no financial conflicts regarding her study.

bjancin@mdedge.com

CHICAGO – The future looks bright for reflectance confocal microscopy (RCM) as a tie breaker to decide whether skin lesions that are equivocal on dermoscopy warrant biopsy to rule out malignancy, Ann M. John, MD, asserted at the annual meeting of the American College of Mohs Surgery.

“With the advent of dermoscopy, dermatologists were able to elucidate both benign and malignant patterns to help further guide their decision to biopsy or not. This increased diagnostic accuracy of suspicious lesions by 30%, while reducing the benign to malignant ratio of biopsies performed from 18:1 to 4:1. However, there are still lesions that are equivocal on dermoscopy, as we all know, and for this, there’s reflectance confocal microscopy,” observed Dr. John, of Robert Wood Johnson Medical School, New Brunswick, N.J.

RCM is a device technology that’s been cleared by the Food and Drug Administration since 2008 for the imaging of clinically suspicious lesions. It employs laser scanning to assess the light-scattering properties of cells in the epidermis and dermis, generating images with resolution comparable to histology.

RCM took a back seat initially while American dermatologists were gradually coming to embrace dermoscopy, which their European colleagues had done years earlier. Now, with the availability of handheld RCM for use in the dermatology clinic, expect RCM to assume a growing role in daily practice.

To illustrate the power of RCM as a diagnostic aid, she presented a single-center retrospective study of 1,189 clinically suspicious skin lesions that were equivocal on dermoscopy and then assessed using RCM with 1 year of subsequent patient follow-up. Overall, 155 lesions were deemed positive for cancer or atypia by RCM, while 1,034 were determined to be benign. Of those 155, 46 lesions were considered false positives because of their benign appearance on histologic inspection of the biopsy sample. Only 2 of the 1,034 lesions identified as negative by RCM proved to be false negatives on the basis of clinical changes within 1 year.

The overall sensitivity and specificity of RCM was 98.2% and 99.8%, respectively, with a positive predictive value of 70.3% and a negative predictive value of 99.8%.

The entire RCM procedure takes a skilled technician 15-20 minutes per lesion. As a practical matter, other investigators have estimated that RCM results in a cost savings of about $308,000 per million health plan members per year by reducing the need for biopsies (Dermatol Clin. 2016 Oct;34[4]:367-75).

In addition to evaluating clinically suspicious lesions, other situations in which RCM offers practical value include its use directly before the first cut during Mohs surgery in order to determine the margins of atypia; ex vivo imaging of Mohs margins, which has been shown to be comparable with frozen sections in accuracy but takes only one-third of the time; and imaging of biopsied lesions in order to determine the diagnosis relatively quickly, Dr. John noted.

She reported having no financial conflicts regarding her study.

bjancin@mdedge.com

CHICAGO – The future looks bright for reflectance confocal microscopy (RCM) as a tie breaker to decide whether skin lesions that are equivocal on dermoscopy warrant biopsy to rule out malignancy, Ann M. John, MD, asserted at the annual meeting of the American College of Mohs Surgery.

“With the advent of dermoscopy, dermatologists were able to elucidate both benign and malignant patterns to help further guide their decision to biopsy or not. This increased diagnostic accuracy of suspicious lesions by 30%, while reducing the benign to malignant ratio of biopsies performed from 18:1 to 4:1. However, there are still lesions that are equivocal on dermoscopy, as we all know, and for this, there’s reflectance confocal microscopy,” observed Dr. John, of Robert Wood Johnson Medical School, New Brunswick, N.J.

RCM is a device technology that’s been cleared by the Food and Drug Administration since 2008 for the imaging of clinically suspicious lesions. It employs laser scanning to assess the light-scattering properties of cells in the epidermis and dermis, generating images with resolution comparable to histology.

RCM took a back seat initially while American dermatologists were gradually coming to embrace dermoscopy, which their European colleagues had done years earlier. Now, with the availability of handheld RCM for use in the dermatology clinic, expect RCM to assume a growing role in daily practice.

To illustrate the power of RCM as a diagnostic aid, she presented a single-center retrospective study of 1,189 clinically suspicious skin lesions that were equivocal on dermoscopy and then assessed using RCM with 1 year of subsequent patient follow-up. Overall, 155 lesions were deemed positive for cancer or atypia by RCM, while 1,034 were determined to be benign. Of those 155, 46 lesions were considered false positives because of their benign appearance on histologic inspection of the biopsy sample. Only 2 of the 1,034 lesions identified as negative by RCM proved to be false negatives on the basis of clinical changes within 1 year.

The overall sensitivity and specificity of RCM was 98.2% and 99.8%, respectively, with a positive predictive value of 70.3% and a negative predictive value of 99.8%.

The entire RCM procedure takes a skilled technician 15-20 minutes per lesion. As a practical matter, other investigators have estimated that RCM results in a cost savings of about $308,000 per million health plan members per year by reducing the need for biopsies (Dermatol Clin. 2016 Oct;34[4]:367-75).

In addition to evaluating clinically suspicious lesions, other situations in which RCM offers practical value include its use directly before the first cut during Mohs surgery in order to determine the margins of atypia; ex vivo imaging of Mohs margins, which has been shown to be comparable with frozen sections in accuracy but takes only one-third of the time; and imaging of biopsied lesions in order to determine the diagnosis relatively quickly, Dr. John noted.

She reported having no financial conflicts regarding her study.

bjancin@mdedge.com

CASE REPORT

A 74-year-old woman presented with a painful lesion on the left lower leg that was getting larger and more edematous and erythematous over the last 5 months. She experienced numbness and burning of the left lower leg 1 year prior to the development of the lesion. A review of her medical history revealed an otherwise healthy woman with no constitutional symptoms of fever, chills, nausea, vomiting, diarrhea, or chest pain. The patient did not exhibit mucosal, genital, or nail involvement. Physical examination revealed a group of four 1-cm, ill-defined, irregularly bordered, violaceous plaques on the left anterior tibial leg with faint surrounding erythematous to violaceous patches (Figure 1). The plaques were tender to palpation with no bleeding or drainage.

An 8.0-mm punch biopsy of the lesion was obtained. Hematoxylin and eosin staining on low-power magnification demonstrated a diffuse lymphocytic inflammatory infiltrate in the dermis and subcutis. Notable sparing of the subepidermal area (free grenz zone) was present (Figure 2A). On higher power, centroblasts and immunoblasts were visualized alongside extravasated red blood cells (Figure 2B). A diagnosis of primary cutaneous diffuse large B-cell lymphoma, leg type (DLBCLLT) was made. Various immunohistochemical stains confirmed the diagnosis, including B-cell lymphoma 2 (BCL-2)(Figure 3A) and multiple myeloma oncogene 1 (MUM-1)(Figure 3B), which were highly positive in our patient. The patient had a negative bone marrow biopsy and positron emission tomography scan. She was started on rituximab infusions and multiple radiation treatments. At 2-year follow-up the lymphoma continued to recur despite radiation therapy.

COMMENT

Incidence and Clinical Characteristics

Primary cutaneous DLBCLLT is an intermediately aggressive form of primary cutaneous B-cell lymphoma (CBCL) that accounts for approximately 10% to 20% of all primary CBCLs and 1% to 3% of all cutaneous lymphomas.¹ Diffuse large B-cell lymphoma, leg type primarily affects elderly patients (median age, 70 years). Women are more commonly affected. Clinically, primary cutaneous DLBCLLT presents as red-brown to bluish nodules or tumors on one or both distal legs. Although referred to as leg-type diffuse large B-cell lymphoma, 10% to 15% of patients have lesions in anatomic areas other than the legs, most commonly the trunk.

Histopathology

The diagnosis of DLBCLLT is best made histologically. There is a dense inflammatory infiltrate present in the dermis and subcutis that may extend upward into the dermoepidermal junction. Often a subepidermal free grenz zone may be seen, and adnexal structures may be destroyed. This infiltrate is composed of confluent sheets of large round cells including centroblasts and immunoblasts.² Centroblasts are large cells that have nuclei with several small nucleoli adhering to the membrane, while immunoblasts are large round cells containing nuclei with large central nucleoli. Both centroblasts and immunoblasts stain positively for BCL-2. Centrocytes typically are absent. Staining for BCL-2 can be important in distinguishing DLBCLLT from other forms of CBCL. Diffuse large B-cell lymphoma, leg type also can demonstrate clusters of large atypical cells in the epidermis simulating epidermotropism and Pautrier microabscesses. Neoplastic cells in this condition may express monoclonal surface and cytoplasmic immunoglobulins. Primary cutaneous DLBCLLT typically is positive for B-cell markers CD20 and CD79a. Additionally, MUM-1/IRF4 (interferon regulatory factor 4) and forkhead box protein 1 (FOXP1) are strongly expressed by most patients, which helps distinguish it from other forms of CBCL.

Treatment

Diffuse large B-cell lymphoma, leg type is a relatively aggressive form of CBCL that requires more aggressive treatment than the conservative watchful waiting of some of the more indolent forms of primary CBCL. One regimen involves using cyclophosphamide, doxorubicin, vincristine, and prednisone plus rituximab. Local chemotherapy or radiation with rituximab is another treatment option.^1,2 In patients with severe comorbidities, rituximab alone may be administered. The prognosis for DLBCLLT is not as favorable as other types of primary CBCL, with an estimated 5-year survival rate of approximately 50%.²

Differential Diagnosis

Lymphomas are malignancies of the lymphocytes that may be subdivided depending on the organ of origin. Both primary nodal lymphomas and primary cutaneous lymphomas exist. Primary nodal lymphomas arise from the lymph nodes and are divided into Hodgkin and non-Hodgkin lymphomas. There are 2 major types of primary cutaneous lymphomas: cutaneous T-cell lymphoma (CTCL) and CBCL. Most primary cutaneous lymphomas are CTCLs, accounting for 75% to 80%.³

Pseudolymphoma
Pseudolymphoma is an inflammatory condition that may histologically mimic cutaneous lymphoma but has a benign clinical course. Pseudolymphoma is not a specific disease but rather is a reactive lymphoproliferative response to a known or unknown stimulus.⁴ Pseudolymphoma can be broken down into 2 or 3 major categories: cutaneous B-cell pseudolymphoma; cutaneous T-cell pseudolymphoma; and debatably lymphomatoid papulosis, a chronic, self-remitting, papulonecrotic condition that resembles lymphoma histologically but clinically appears benign. It is unknown if lymphomatoid papulosis represents a pseudolymphoma or a true lymphoma. Lymphomatoid papulosis may represent an early indolent form of CTCL.⁴

Pseudolymphomas can be triggered by a variety of causes. Most cases are idiopathic, and a causative stimulus is never identified. Drugs are known to cause many cases of pseudolymphoma, either by a causing a hypersensitivity reaction or by depressing immunosurveillance.⁵ Pseudolymphomas may result from exogenous stimuli such as jewelry, tattoo dyes, injectable fillers (eg, silicone), insect bites, vaccines, and trauma.^6,7 Lastly, infections in the form of Borrelia, varicella, and molluscum contagiosum can potentially cause pseudolymphomas.⁴

Clinically, pseudolymphomas may demonstrate a B-cell or T-cell pattern. In cutaneous B-cell pseudolymphomas, asymptomatic solitary erythematous, violaceous, or flesh-colored nodules appear on the face, followed by the chest and arms. Cutaneous T-cell pseudolymphomas present with erythematous patches that are more likely to be symptomatic.⁴

Histologically, pseudolymphomas also are classified as demonstrating B-cell or T-cell patterns. The nodular inflammatory infiltrate of cutaneous B-cell pseudolymphoma corresponds with its clinically apparent nodules. It can be distinguished from lymphoma in that it is not solely a lymphocytic infiltrate but rather a mixed infiltrate including histiocytes, lymphocytes, eosinophils, and plasma cells. Additionally, cutaneous B-cell pseudolymphoma does not penetrate the dermis as deeply as CBCL.⁸ Cutaneous T-cell pseudolymphoma is more difficult to distinguish from CTCL because it also demonstrates a bandlike lymphocytic infiltrate in the papillary dermis with epidermotropism.⁹

Treatment must address the underlying cause of pseudolymphoma for resolution. Other treatment options include surgery, cryotherapy, local radiotherapy, topical steroids, and topical immunomodulators. Spontaneous resolution also can occur. The prognosis is better when a known trigger is eliminated, though idiopathic pseudolymphomas may be chronic in nature. It is important to rule out concurrent cutaneous lymphoma or rare transformation into cutaneous lymphoma.

Cutaneous T-Cell Lymphoma
Cutaneous T-cell lymphomas are a diverse group of neoplasms that account for most cutaneous lymphomas seen by dermatologists. In 1806, the first case of CTCL in the form of mycosis fungoides (MF) was described by Jean Louis Alibert. Mycosis fungoides represents the most common form of CTCL, accounting for approximately 50% of all primary cutaneous lymphomas.¹⁰ Mycosis fungoides was named after its morphological resemblance to mushrooms. Although not all cases exhibit a classic progression, MF is known for its stepwise progression from patch stage to tumor stage.

Clinically, lesions typically begin as patches that progress to plaques and finally tumors. This progression may not always occur and often can take years to decades to progress. Patches are characterized by erythematous, finely scaling lesions that may be easily confused with eczema or psoriasis. Lesions occur primarily in a swimming trunk distribution.

Mycosis fungoides histologically demonstrates a bandlike lymphocytic infiltrate with epidermotropism, which occurs when lymphocytes infiltrate the epidermis without spongiosis. These lymphocytes are larger, darker, and more angulated than normal lymphocytes. Intraepidermal nests of these atypical lymphocytes creating Pautrier microabscesses may be present. Tumor-stage lesions demonstrate diminished epidermotropism with dense sheets of lymphocytes in the dermis, and fat cells with cerebriform nuclei are present.

Therapies for MF may control the disease but may not prolong patients’ lives. Topical corticosteroids, phototherapy, and radiotherapy are options for skin-targeting therapies. Systemic chemotherapy and biological response modifiers also are viable treatment options. Prognosis for MF is poor.

There are a few notable variants of MF that are important to consider. Sézary syndrome is an erythrodermic variant of MF characterized by atypical Sézary cells. Clinically, it presents with generalized erythroderma with leonine facies, facial edema, and alopecia with associated symptoms of burning and pruritus. Histologically, Sézary syndrome is similar to MF with an increased CD4:CD8 ratio.¹⁰ Sézary syndrome may be treated with methotrexate or photopheresis, but the prognosis remains poor with an average survival of 5 years.

Cutaneous B-Cell Lymphoma
There are 5 types of primary CBCL: primary cutaneous follicle center lymphoma; primary cutaneous marginal zone B-cell lymphoma; primary cutaneous diffuse large B-cell lymphoma, other; precursor B-cell lymphoblastic lymphoma; and primary cutaneous DLBCLLT, which was seen in our patient.¹¹

Primary cutaneous follicle center lymphoma is an indolent neoplastic proliferation in the skin. Clinically, it presents with solitary or grouped pinkish purple papules, plaques, or nodules on the trunk with surrounding patches of erythema.³ Lesions located on the back are referred to as Crosti lymphoma. Histopathology reveals a lymphocytic infiltrate with a diffuse follicular pattern and large round centroblasts, centrocytes, and immunoblasts with epidermal sparing. Tumor cells stain positively for κ or λ light chains, as well as CD20, CD79a, and B-cell lymphoma 6 (BCL-6); however, staining for the protein product of BCL-2 may be negative, which differentiates this form of CBCL from primary nodal B-cell lymphoma. Staining for MUM-1 may be negative, which contrasts with the strong expression seen in DLBCLLT. The follicular pattern of follicle center lymphoma stains positive for CD10, but the diffuse pattern may be CD10 negative. The prognosis for primary cutaneous follicle center lymphoma is favorable, but the recurrence rate is up to 50%.³ Treatment includes local radiotherapy or surgical excision.

Primary cutaneous marginal zone B-cell lymphoma is another indolent primary CBCL subtype that is closely related to mucosa-associated lymphoid tissue lymphomas and arises in areas of acrodermatitis chronica atrophicans and Borrelia infection. Clinically, it presents with recurrent, asymptomatic, red-brown papules, plaques, and nodules of the arms and legs. Histologically, there is a patchy infiltrate in the dermis and subcutis with sparing of the epidermis with pale-staining cells with indented nuclei, along with plasma cells and eosinophils. Primary cutaneous marginal zone B-cell lymphoma typically does not demonstrate epidermotropism. Centrocyte cells stain positively for CD20, CD79a, and BCL-2. The prognosis of primary cutaneous marginal zone B-cell lymphoma is favorable. Treatment is similar to primary cutaneous follicle center lymphoma with surgical excision, radiotherapy, and surveillance being the main modalities.

Primary cutaneous diffuse large B-cell lymphoma, other is an intermediately aggressive form of primary CBCL that is thought to be related to primary cutaneous DLBCLLT. Clinically, it presents with indurated erythematous to violaceous plaques on the trunk and thighs that may resemble a vascular tumor or panniculitis.^2,12 Histopathologically, this form of lymphoma presents with a round cell morphology without BCL-2 expression, which distinguishes it from DLBCLLT. If limited to skin, the prognosis is better than the systemic form but is still less favorable than other forms of CBCL.

Precursor B-cell lymphoblastic lymphoma is an extremely rare type of CBCL that potentially can occur in the skin. It primarily affects children and young adults. Clinically, it presents as a solitary large erythematous tumor of the head. Histologically, monomorphic proliferation of medium-sized cells with round nuclei that demonstrate a starry sky pattern with multiple mitotic cells can be observed.¹³ Immunohistochemical markers such as CD43, CD10, CD20, and CD79a may be positive. The disease is very aggressive with poor prognosis if left untreated.

CONCLUSION

We present a rare case of primary cutaneous DLBCLLT. Our case demonstrates the classic presentation of primary cutaneous DLBCLLT in a 74-year-old woman with a tumor on the lower left leg. Histologically, a dense dermal and subcutis infiltrate of centroblasts and immunoblasts with a grenz zone was present. Immunostaining in our patient was consistent with characteristic findings in the literature, staining highly positive for BCL-2 and MUM-1. Primary cutaneous DLBCLLT is an extremely rare and unique form of cutaneous lymphoma that can have potentially fatal consequences if undiagnosed; therefore, clinicians must take great care to make the correct diagnosis based on a knowledge of the clinical and immunohistochemical findings of DLBCLLT.

CASE REPORT

A 74-year-old woman presented with a painful lesion on the left lower leg that was getting larger and more edematous and erythematous over the last 5 months. She experienced numbness and burning of the left lower leg 1 year prior to the development of the lesion. A review of her medical history revealed an otherwise healthy woman with no constitutional symptoms of fever, chills, nausea, vomiting, diarrhea, or chest pain. The patient did not exhibit mucosal, genital, or nail involvement. Physical examination revealed a group of four 1-cm, ill-defined, irregularly bordered, violaceous plaques on the left anterior tibial leg with faint surrounding erythematous to violaceous patches (Figure 1). The plaques were tender to palpation with no bleeding or drainage.

An 8.0-mm punch biopsy of the lesion was obtained. Hematoxylin and eosin staining on low-power magnification demonstrated a diffuse lymphocytic inflammatory infiltrate in the dermis and subcutis. Notable sparing of the subepidermal area (free grenz zone) was present (Figure 2A). On higher power, centroblasts and immunoblasts were visualized alongside extravasated red blood cells (Figure 2B). A diagnosis of primary cutaneous diffuse large B-cell lymphoma, leg type (DLBCLLT) was made. Various immunohistochemical stains confirmed the diagnosis, including B-cell lymphoma 2 (BCL-2)(Figure 3A) and multiple myeloma oncogene 1 (MUM-1)(Figure 3B), which were highly positive in our patient. The patient had a negative bone marrow biopsy and positron emission tomography scan. She was started on rituximab infusions and multiple radiation treatments. At 2-year follow-up the lymphoma continued to recur despite radiation therapy.

COMMENT

Incidence and Clinical Characteristics

Primary cutaneous DLBCLLT is an intermediately aggressive form of primary cutaneous B-cell lymphoma (CBCL) that accounts for approximately 10% to 20% of all primary CBCLs and 1% to 3% of all cutaneous lymphomas.¹ Diffuse large B-cell lymphoma, leg type primarily affects elderly patients (median age, 70 years). Women are more commonly affected. Clinically, primary cutaneous DLBCLLT presents as red-brown to bluish nodules or tumors on one or both distal legs. Although referred to as leg-type diffuse large B-cell lymphoma, 10% to 15% of patients have lesions in anatomic areas other than the legs, most commonly the trunk.

Histopathology

The diagnosis of DLBCLLT is best made histologically. There is a dense inflammatory infiltrate present in the dermis and subcutis that may extend upward into the dermoepidermal junction. Often a subepidermal free grenz zone may be seen, and adnexal structures may be destroyed. This infiltrate is composed of confluent sheets of large round cells including centroblasts and immunoblasts.² Centroblasts are large cells that have nuclei with several small nucleoli adhering to the membrane, while immunoblasts are large round cells containing nuclei with large central nucleoli. Both centroblasts and immunoblasts stain positively for BCL-2. Centrocytes typically are absent. Staining for BCL-2 can be important in distinguishing DLBCLLT from other forms of CBCL. Diffuse large B-cell lymphoma, leg type also can demonstrate clusters of large atypical cells in the epidermis simulating epidermotropism and Pautrier microabscesses. Neoplastic cells in this condition may express monoclonal surface and cytoplasmic immunoglobulins. Primary cutaneous DLBCLLT typically is positive for B-cell markers CD20 and CD79a. Additionally, MUM-1/IRF4 (interferon regulatory factor 4) and forkhead box protein 1 (FOXP1) are strongly expressed by most patients, which helps distinguish it from other forms of CBCL.

Treatment

Diffuse large B-cell lymphoma, leg type is a relatively aggressive form of CBCL that requires more aggressive treatment than the conservative watchful waiting of some of the more indolent forms of primary CBCL. One regimen involves using cyclophosphamide, doxorubicin, vincristine, and prednisone plus rituximab. Local chemotherapy or radiation with rituximab is another treatment option.^1,2 In patients with severe comorbidities, rituximab alone may be administered. The prognosis for DLBCLLT is not as favorable as other types of primary CBCL, with an estimated 5-year survival rate of approximately 50%.²

Differential Diagnosis

Lymphomas are malignancies of the lymphocytes that may be subdivided depending on the organ of origin. Both primary nodal lymphomas and primary cutaneous lymphomas exist. Primary nodal lymphomas arise from the lymph nodes and are divided into Hodgkin and non-Hodgkin lymphomas. There are 2 major types of primary cutaneous lymphomas: cutaneous T-cell lymphoma (CTCL) and CBCL. Most primary cutaneous lymphomas are CTCLs, accounting for 75% to 80%.³

Pseudolymphoma
Pseudolymphoma is an inflammatory condition that may histologically mimic cutaneous lymphoma but has a benign clinical course. Pseudolymphoma is not a specific disease but rather is a reactive lymphoproliferative response to a known or unknown stimulus.⁴ Pseudolymphoma can be broken down into 2 or 3 major categories: cutaneous B-cell pseudolymphoma; cutaneous T-cell pseudolymphoma; and debatably lymphomatoid papulosis, a chronic, self-remitting, papulonecrotic condition that resembles lymphoma histologically but clinically appears benign. It is unknown if lymphomatoid papulosis represents a pseudolymphoma or a true lymphoma. Lymphomatoid papulosis may represent an early indolent form of CTCL.⁴

Pseudolymphomas can be triggered by a variety of causes. Most cases are idiopathic, and a causative stimulus is never identified. Drugs are known to cause many cases of pseudolymphoma, either by a causing a hypersensitivity reaction or by depressing immunosurveillance.⁵ Pseudolymphomas may result from exogenous stimuli such as jewelry, tattoo dyes, injectable fillers (eg, silicone), insect bites, vaccines, and trauma.^6,7 Lastly, infections in the form of Borrelia, varicella, and molluscum contagiosum can potentially cause pseudolymphomas.⁴

Clinically, pseudolymphomas may demonstrate a B-cell or T-cell pattern. In cutaneous B-cell pseudolymphomas, asymptomatic solitary erythematous, violaceous, or flesh-colored nodules appear on the face, followed by the chest and arms. Cutaneous T-cell pseudolymphomas present with erythematous patches that are more likely to be symptomatic.⁴

Histologically, pseudolymphomas also are classified as demonstrating B-cell or T-cell patterns. The nodular inflammatory infiltrate of cutaneous B-cell pseudolymphoma corresponds with its clinically apparent nodules. It can be distinguished from lymphoma in that it is not solely a lymphocytic infiltrate but rather a mixed infiltrate including histiocytes, lymphocytes, eosinophils, and plasma cells. Additionally, cutaneous B-cell pseudolymphoma does not penetrate the dermis as deeply as CBCL.⁸ Cutaneous T-cell pseudolymphoma is more difficult to distinguish from CTCL because it also demonstrates a bandlike lymphocytic infiltrate in the papillary dermis with epidermotropism.⁹

Treatment must address the underlying cause of pseudolymphoma for resolution. Other treatment options include surgery, cryotherapy, local radiotherapy, topical steroids, and topical immunomodulators. Spontaneous resolution also can occur. The prognosis is better when a known trigger is eliminated, though idiopathic pseudolymphomas may be chronic in nature. It is important to rule out concurrent cutaneous lymphoma or rare transformation into cutaneous lymphoma.

Cutaneous T-Cell Lymphoma
Cutaneous T-cell lymphomas are a diverse group of neoplasms that account for most cutaneous lymphomas seen by dermatologists. In 1806, the first case of CTCL in the form of mycosis fungoides (MF) was described by Jean Louis Alibert. Mycosis fungoides represents the most common form of CTCL, accounting for approximately 50% of all primary cutaneous lymphomas.¹⁰ Mycosis fungoides was named after its morphological resemblance to mushrooms. Although not all cases exhibit a classic progression, MF is known for its stepwise progression from patch stage to tumor stage.

Clinically, lesions typically begin as patches that progress to plaques and finally tumors. This progression may not always occur and often can take years to decades to progress. Patches are characterized by erythematous, finely scaling lesions that may be easily confused with eczema or psoriasis. Lesions occur primarily in a swimming trunk distribution.

Mycosis fungoides histologically demonstrates a bandlike lymphocytic infiltrate with epidermotropism, which occurs when lymphocytes infiltrate the epidermis without spongiosis. These lymphocytes are larger, darker, and more angulated than normal lymphocytes. Intraepidermal nests of these atypical lymphocytes creating Pautrier microabscesses may be present. Tumor-stage lesions demonstrate diminished epidermotropism with dense sheets of lymphocytes in the dermis, and fat cells with cerebriform nuclei are present.

Therapies for MF may control the disease but may not prolong patients’ lives. Topical corticosteroids, phototherapy, and radiotherapy are options for skin-targeting therapies. Systemic chemotherapy and biological response modifiers also are viable treatment options. Prognosis for MF is poor.

There are a few notable variants of MF that are important to consider. Sézary syndrome is an erythrodermic variant of MF characterized by atypical Sézary cells. Clinically, it presents with generalized erythroderma with leonine facies, facial edema, and alopecia with associated symptoms of burning and pruritus. Histologically, Sézary syndrome is similar to MF with an increased CD4:CD8 ratio.¹⁰ Sézary syndrome may be treated with methotrexate or photopheresis, but the prognosis remains poor with an average survival of 5 years.

Cutaneous B-Cell Lymphoma
There are 5 types of primary CBCL: primary cutaneous follicle center lymphoma; primary cutaneous marginal zone B-cell lymphoma; primary cutaneous diffuse large B-cell lymphoma, other; precursor B-cell lymphoblastic lymphoma; and primary cutaneous DLBCLLT, which was seen in our patient.¹¹

Primary cutaneous follicle center lymphoma is an indolent neoplastic proliferation in the skin. Clinically, it presents with solitary or grouped pinkish purple papules, plaques, or nodules on the trunk with surrounding patches of erythema.³ Lesions located on the back are referred to as Crosti lymphoma. Histopathology reveals a lymphocytic infiltrate with a diffuse follicular pattern and large round centroblasts, centrocytes, and immunoblasts with epidermal sparing. Tumor cells stain positively for κ or λ light chains, as well as CD20, CD79a, and B-cell lymphoma 6 (BCL-6); however, staining for the protein product of BCL-2 may be negative, which differentiates this form of CBCL from primary nodal B-cell lymphoma. Staining for MUM-1 may be negative, which contrasts with the strong expression seen in DLBCLLT. The follicular pattern of follicle center lymphoma stains positive for CD10, but the diffuse pattern may be CD10 negative. The prognosis for primary cutaneous follicle center lymphoma is favorable, but the recurrence rate is up to 50%.³ Treatment includes local radiotherapy or surgical excision.

Primary cutaneous marginal zone B-cell lymphoma is another indolent primary CBCL subtype that is closely related to mucosa-associated lymphoid tissue lymphomas and arises in areas of acrodermatitis chronica atrophicans and Borrelia infection. Clinically, it presents with recurrent, asymptomatic, red-brown papules, plaques, and nodules of the arms and legs. Histologically, there is a patchy infiltrate in the dermis and subcutis with sparing of the epidermis with pale-staining cells with indented nuclei, along with plasma cells and eosinophils. Primary cutaneous marginal zone B-cell lymphoma typically does not demonstrate epidermotropism. Centrocyte cells stain positively for CD20, CD79a, and BCL-2. The prognosis of primary cutaneous marginal zone B-cell lymphoma is favorable. Treatment is similar to primary cutaneous follicle center lymphoma with surgical excision, radiotherapy, and surveillance being the main modalities.

Primary cutaneous diffuse large B-cell lymphoma, other is an intermediately aggressive form of primary CBCL that is thought to be related to primary cutaneous DLBCLLT. Clinically, it presents with indurated erythematous to violaceous plaques on the trunk and thighs that may resemble a vascular tumor or panniculitis.^2,12 Histopathologically, this form of lymphoma presents with a round cell morphology without BCL-2 expression, which distinguishes it from DLBCLLT. If limited to skin, the prognosis is better than the systemic form but is still less favorable than other forms of CBCL.

Precursor B-cell lymphoblastic lymphoma is an extremely rare type of CBCL that potentially can occur in the skin. It primarily affects children and young adults. Clinically, it presents as a solitary large erythematous tumor of the head. Histologically, monomorphic proliferation of medium-sized cells with round nuclei that demonstrate a starry sky pattern with multiple mitotic cells can be observed.¹³ Immunohistochemical markers such as CD43, CD10, CD20, and CD79a may be positive. The disease is very aggressive with poor prognosis if left untreated.

CONCLUSION

We present a rare case of primary cutaneous DLBCLLT. Our case demonstrates the classic presentation of primary cutaneous DLBCLLT in a 74-year-old woman with a tumor on the lower left leg. Histologically, a dense dermal and subcutis infiltrate of centroblasts and immunoblasts with a grenz zone was present. Immunostaining in our patient was consistent with characteristic findings in the literature, staining highly positive for BCL-2 and MUM-1. Primary cutaneous DLBCLLT is an extremely rare and unique form of cutaneous lymphoma that can have potentially fatal consequences if undiagnosed; therefore, clinicians must take great care to make the correct diagnosis based on a knowledge of the clinical and immunohistochemical findings of DLBCLLT.

CASE REPORT

A 74-year-old woman presented with a painful lesion on the left lower leg that was getting larger and more edematous and erythematous over the last 5 months. She experienced numbness and burning of the left lower leg 1 year prior to the development of the lesion. A review of her medical history revealed an otherwise healthy woman with no constitutional symptoms of fever, chills, nausea, vomiting, diarrhea, or chest pain. The patient did not exhibit mucosal, genital, or nail involvement. Physical examination revealed a group of four 1-cm, ill-defined, irregularly bordered, violaceous plaques on the left anterior tibial leg with faint surrounding erythematous to violaceous patches (Figure 1). The plaques were tender to palpation with no bleeding or drainage.

An 8.0-mm punch biopsy of the lesion was obtained. Hematoxylin and eosin staining on low-power magnification demonstrated a diffuse lymphocytic inflammatory infiltrate in the dermis and subcutis. Notable sparing of the subepidermal area (free grenz zone) was present (Figure 2A). On higher power, centroblasts and immunoblasts were visualized alongside extravasated red blood cells (Figure 2B). A diagnosis of primary cutaneous diffuse large B-cell lymphoma, leg type (DLBCLLT) was made. Various immunohistochemical stains confirmed the diagnosis, including B-cell lymphoma 2 (BCL-2)(Figure 3A) and multiple myeloma oncogene 1 (MUM-1)(Figure 3B), which were highly positive in our patient. The patient had a negative bone marrow biopsy and positron emission tomography scan. She was started on rituximab infusions and multiple radiation treatments. At 2-year follow-up the lymphoma continued to recur despite radiation therapy.

COMMENT

Incidence and Clinical Characteristics

Primary cutaneous DLBCLLT is an intermediately aggressive form of primary cutaneous B-cell lymphoma (CBCL) that accounts for approximately 10% to 20% of all primary CBCLs and 1% to 3% of all cutaneous lymphomas.¹ Diffuse large B-cell lymphoma, leg type primarily affects elderly patients (median age, 70 years). Women are more commonly affected. Clinically, primary cutaneous DLBCLLT presents as red-brown to bluish nodules or tumors on one or both distal legs. Although referred to as leg-type diffuse large B-cell lymphoma, 10% to 15% of patients have lesions in anatomic areas other than the legs, most commonly the trunk.

Histopathology

The diagnosis of DLBCLLT is best made histologically. There is a dense inflammatory infiltrate present in the dermis and subcutis that may extend upward into the dermoepidermal junction. Often a subepidermal free grenz zone may be seen, and adnexal structures may be destroyed. This infiltrate is composed of confluent sheets of large round cells including centroblasts and immunoblasts.² Centroblasts are large cells that have nuclei with several small nucleoli adhering to the membrane, while immunoblasts are large round cells containing nuclei with large central nucleoli. Both centroblasts and immunoblasts stain positively for BCL-2. Centrocytes typically are absent. Staining for BCL-2 can be important in distinguishing DLBCLLT from other forms of CBCL. Diffuse large B-cell lymphoma, leg type also can demonstrate clusters of large atypical cells in the epidermis simulating epidermotropism and Pautrier microabscesses. Neoplastic cells in this condition may express monoclonal surface and cytoplasmic immunoglobulins. Primary cutaneous DLBCLLT typically is positive for B-cell markers CD20 and CD79a. Additionally, MUM-1/IRF4 (interferon regulatory factor 4) and forkhead box protein 1 (FOXP1) are strongly expressed by most patients, which helps distinguish it from other forms of CBCL.

Treatment

Diffuse large B-cell lymphoma, leg type is a relatively aggressive form of CBCL that requires more aggressive treatment than the conservative watchful waiting of some of the more indolent forms of primary CBCL. One regimen involves using cyclophosphamide, doxorubicin, vincristine, and prednisone plus rituximab. Local chemotherapy or radiation with rituximab is another treatment option.^1,2 In patients with severe comorbidities, rituximab alone may be administered. The prognosis for DLBCLLT is not as favorable as other types of primary CBCL, with an estimated 5-year survival rate of approximately 50%.²

Differential Diagnosis

Lymphomas are malignancies of the lymphocytes that may be subdivided depending on the organ of origin. Both primary nodal lymphomas and primary cutaneous lymphomas exist. Primary nodal lymphomas arise from the lymph nodes and are divided into Hodgkin and non-Hodgkin lymphomas. There are 2 major types of primary cutaneous lymphomas: cutaneous T-cell lymphoma (CTCL) and CBCL. Most primary cutaneous lymphomas are CTCLs, accounting for 75% to 80%.³

Pseudolymphoma
Pseudolymphoma is an inflammatory condition that may histologically mimic cutaneous lymphoma but has a benign clinical course. Pseudolymphoma is not a specific disease but rather is a reactive lymphoproliferative response to a known or unknown stimulus.⁴ Pseudolymphoma can be broken down into 2 or 3 major categories: cutaneous B-cell pseudolymphoma; cutaneous T-cell pseudolymphoma; and debatably lymphomatoid papulosis, a chronic, self-remitting, papulonecrotic condition that resembles lymphoma histologically but clinically appears benign. It is unknown if lymphomatoid papulosis represents a pseudolymphoma or a true lymphoma. Lymphomatoid papulosis may represent an early indolent form of CTCL.⁴

Pseudolymphomas can be triggered by a variety of causes. Most cases are idiopathic, and a causative stimulus is never identified. Drugs are known to cause many cases of pseudolymphoma, either by a causing a hypersensitivity reaction or by depressing immunosurveillance.⁵ Pseudolymphomas may result from exogenous stimuli such as jewelry, tattoo dyes, injectable fillers (eg, silicone), insect bites, vaccines, and trauma.^6,7 Lastly, infections in the form of Borrelia, varicella, and molluscum contagiosum can potentially cause pseudolymphomas.⁴

Clinically, pseudolymphomas may demonstrate a B-cell or T-cell pattern. In cutaneous B-cell pseudolymphomas, asymptomatic solitary erythematous, violaceous, or flesh-colored nodules appear on the face, followed by the chest and arms. Cutaneous T-cell pseudolymphomas present with erythematous patches that are more likely to be symptomatic.⁴

Histologically, pseudolymphomas also are classified as demonstrating B-cell or T-cell patterns. The nodular inflammatory infiltrate of cutaneous B-cell pseudolymphoma corresponds with its clinically apparent nodules. It can be distinguished from lymphoma in that it is not solely a lymphocytic infiltrate but rather a mixed infiltrate including histiocytes, lymphocytes, eosinophils, and plasma cells. Additionally, cutaneous B-cell pseudolymphoma does not penetrate the dermis as deeply as CBCL.⁸ Cutaneous T-cell pseudolymphoma is more difficult to distinguish from CTCL because it also demonstrates a bandlike lymphocytic infiltrate in the papillary dermis with epidermotropism.⁹

Treatment must address the underlying cause of pseudolymphoma for resolution. Other treatment options include surgery, cryotherapy, local radiotherapy, topical steroids, and topical immunomodulators. Spontaneous resolution also can occur. The prognosis is better when a known trigger is eliminated, though idiopathic pseudolymphomas may be chronic in nature. It is important to rule out concurrent cutaneous lymphoma or rare transformation into cutaneous lymphoma.

Cutaneous T-Cell Lymphoma
Cutaneous T-cell lymphomas are a diverse group of neoplasms that account for most cutaneous lymphomas seen by dermatologists. In 1806, the first case of CTCL in the form of mycosis fungoides (MF) was described by Jean Louis Alibert. Mycosis fungoides represents the most common form of CTCL, accounting for approximately 50% of all primary cutaneous lymphomas.¹⁰ Mycosis fungoides was named after its morphological resemblance to mushrooms. Although not all cases exhibit a classic progression, MF is known for its stepwise progression from patch stage to tumor stage.

Clinically, lesions typically begin as patches that progress to plaques and finally tumors. This progression may not always occur and often can take years to decades to progress. Patches are characterized by erythematous, finely scaling lesions that may be easily confused with eczema or psoriasis. Lesions occur primarily in a swimming trunk distribution.

Mycosis fungoides histologically demonstrates a bandlike lymphocytic infiltrate with epidermotropism, which occurs when lymphocytes infiltrate the epidermis without spongiosis. These lymphocytes are larger, darker, and more angulated than normal lymphocytes. Intraepidermal nests of these atypical lymphocytes creating Pautrier microabscesses may be present. Tumor-stage lesions demonstrate diminished epidermotropism with dense sheets of lymphocytes in the dermis, and fat cells with cerebriform nuclei are present.

Therapies for MF may control the disease but may not prolong patients’ lives. Topical corticosteroids, phototherapy, and radiotherapy are options for skin-targeting therapies. Systemic chemotherapy and biological response modifiers also are viable treatment options. Prognosis for MF is poor.

There are a few notable variants of MF that are important to consider. Sézary syndrome is an erythrodermic variant of MF characterized by atypical Sézary cells. Clinically, it presents with generalized erythroderma with leonine facies, facial edema, and alopecia with associated symptoms of burning and pruritus. Histologically, Sézary syndrome is similar to MF with an increased CD4:CD8 ratio.¹⁰ Sézary syndrome may be treated with methotrexate or photopheresis, but the prognosis remains poor with an average survival of 5 years.

Cutaneous B-Cell Lymphoma
There are 5 types of primary CBCL: primary cutaneous follicle center lymphoma; primary cutaneous marginal zone B-cell lymphoma; primary cutaneous diffuse large B-cell lymphoma, other; precursor B-cell lymphoblastic lymphoma; and primary cutaneous DLBCLLT, which was seen in our patient.¹¹

Primary cutaneous follicle center lymphoma is an indolent neoplastic proliferation in the skin. Clinically, it presents with solitary or grouped pinkish purple papules, plaques, or nodules on the trunk with surrounding patches of erythema.³ Lesions located on the back are referred to as Crosti lymphoma. Histopathology reveals a lymphocytic infiltrate with a diffuse follicular pattern and large round centroblasts, centrocytes, and immunoblasts with epidermal sparing. Tumor cells stain positively for κ or λ light chains, as well as CD20, CD79a, and B-cell lymphoma 6 (BCL-6); however, staining for the protein product of BCL-2 may be negative, which differentiates this form of CBCL from primary nodal B-cell lymphoma. Staining for MUM-1 may be negative, which contrasts with the strong expression seen in DLBCLLT. The follicular pattern of follicle center lymphoma stains positive for CD10, but the diffuse pattern may be CD10 negative. The prognosis for primary cutaneous follicle center lymphoma is favorable, but the recurrence rate is up to 50%.³ Treatment includes local radiotherapy or surgical excision.

Primary cutaneous marginal zone B-cell lymphoma is another indolent primary CBCL subtype that is closely related to mucosa-associated lymphoid tissue lymphomas and arises in areas of acrodermatitis chronica atrophicans and Borrelia infection. Clinically, it presents with recurrent, asymptomatic, red-brown papules, plaques, and nodules of the arms and legs. Histologically, there is a patchy infiltrate in the dermis and subcutis with sparing of the epidermis with pale-staining cells with indented nuclei, along with plasma cells and eosinophils. Primary cutaneous marginal zone B-cell lymphoma typically does not demonstrate epidermotropism. Centrocyte cells stain positively for CD20, CD79a, and BCL-2. The prognosis of primary cutaneous marginal zone B-cell lymphoma is favorable. Treatment is similar to primary cutaneous follicle center lymphoma with surgical excision, radiotherapy, and surveillance being the main modalities.

Primary cutaneous diffuse large B-cell lymphoma, other is an intermediately aggressive form of primary CBCL that is thought to be related to primary cutaneous DLBCLLT. Clinically, it presents with indurated erythematous to violaceous plaques on the trunk and thighs that may resemble a vascular tumor or panniculitis.^2,12 Histopathologically, this form of lymphoma presents with a round cell morphology without BCL-2 expression, which distinguishes it from DLBCLLT. If limited to skin, the prognosis is better than the systemic form but is still less favorable than other forms of CBCL.

Precursor B-cell lymphoblastic lymphoma is an extremely rare type of CBCL that potentially can occur in the skin. It primarily affects children and young adults. Clinically, it presents as a solitary large erythematous tumor of the head. Histologically, monomorphic proliferation of medium-sized cells with round nuclei that demonstrate a starry sky pattern with multiple mitotic cells can be observed.¹³ Immunohistochemical markers such as CD43, CD10, CD20, and CD79a may be positive. The disease is very aggressive with poor prognosis if left untreated.

CONCLUSION

We present a rare case of primary cutaneous DLBCLLT. Our case demonstrates the classic presentation of primary cutaneous DLBCLLT in a 74-year-old woman with a tumor on the lower left leg. Histologically, a dense dermal and subcutis infiltrate of centroblasts and immunoblasts with a grenz zone was present. Immunostaining in our patient was consistent with characteristic findings in the literature, staining highly positive for BCL-2 and MUM-1. Primary cutaneous DLBCLLT is an extremely rare and unique form of cutaneous lymphoma that can have potentially fatal consequences if undiagnosed; therefore, clinicians must take great care to make the correct diagnosis based on a knowledge of the clinical and immunohistochemical findings of DLBCLLT.

CHICAGO – Oral itraconazole shows potential for treatment of locally advanced or metastatic basal cell carcinoma (BCC) as well as Gorlin syndrome, Justin J. Leitenberger, MD, declared at the annual meeting of the American College of Mohs Surgery.

Bruce Jancin/MDedge News

The oral antifungal inhibits the hedgehog signaling pathway, a key driver of BCC. And while itraconazole is not as potent an inhibitor of hedgehog pathway expression as, say vismodegib (Erivedge), the antifungal acts at a separate site on the pathway, making it an attractive candidate for combination therapy, explained Dr. Leitenberger of Oregon Health & Science University, Portland.

Dermatologists at Stanford University have led the way in exploring oral itraconazole as a treatment for BCC. Among a series of 29 patients with one or more large but nonadvanced BCCs, 19 were treated using oral itraconazole at 200 mg b.i.d. for 1 month or 100 mg b.i.d. for an average of 2.3 months. Hedgehog pathway expression was reduced by 65% in the itraconazole-treated patients, as compared with the 90% reduction which is achieved with vismodegib.

Of more direct clinical relevance, however, itraconazole also reduced tumor area by 24%. Four of eight patients with 57 tumors achieved a partial response, and the other four had stable disease (J Clin Oncol. 2014 Mar 10;32[8]:745-51).

The Stanford group has also shown that combination therapy with oral itraconazole and intravenous arsenic trioxide reduces hedgehog pathway expression by 75%, up by an absolute 10% from itraconazole alone. The two agents inhibit the pathway at different sites.

Five patients with metastatic BCC who relapsed after treatment with vismodegib received intravenous arsenic trioxide for the first 5 days of every month, followed by oral itraconazole at 200 mg b.i.d. on days 6-28. Three patients completed three such cycles, while two discontinued early because of progressive disease or adverse events including a grade 3 infection and grade 2 transaminitis. All three patients who completed three treatment cycles achieved stable disease. The Stanford investigators speculated that concurrent continuous dosing might be required to obtain tumor shrinkage (JAMA Dermatol. 2016 Apr;152[4]:452-6).

Lots more work remains to be done in order to optimize combination therapy utilizing oral itraconazole for advanced BCC. Different dosing regimens and combinations of hedgehog pathway inhibitors need to be studied. Another important question is how effective itraconazole-based combinations will be in vismodegib-naive as compared with vismodegib-resistant patients, Dr. Leitenberger observed.

He reported having no financial conflicts regarding his presentation.

bjancin@mdedge.com

CHICAGO – Oral itraconazole shows potential for treatment of locally advanced or metastatic basal cell carcinoma (BCC) as well as Gorlin syndrome, Justin J. Leitenberger, MD, declared at the annual meeting of the American College of Mohs Surgery.

Bruce Jancin/MDedge News

The oral antifungal inhibits the hedgehog signaling pathway, a key driver of BCC. And while itraconazole is not as potent an inhibitor of hedgehog pathway expression as, say vismodegib (Erivedge), the antifungal acts at a separate site on the pathway, making it an attractive candidate for combination therapy, explained Dr. Leitenberger of Oregon Health & Science University, Portland.

Dermatologists at Stanford University have led the way in exploring oral itraconazole as a treatment for BCC. Among a series of 29 patients with one or more large but nonadvanced BCCs, 19 were treated using oral itraconazole at 200 mg b.i.d. for 1 month or 100 mg b.i.d. for an average of 2.3 months. Hedgehog pathway expression was reduced by 65% in the itraconazole-treated patients, as compared with the 90% reduction which is achieved with vismodegib.

Of more direct clinical relevance, however, itraconazole also reduced tumor area by 24%. Four of eight patients with 57 tumors achieved a partial response, and the other four had stable disease (J Clin Oncol. 2014 Mar 10;32[8]:745-51).

The Stanford group has also shown that combination therapy with oral itraconazole and intravenous arsenic trioxide reduces hedgehog pathway expression by 75%, up by an absolute 10% from itraconazole alone. The two agents inhibit the pathway at different sites.

Five patients with metastatic BCC who relapsed after treatment with vismodegib received intravenous arsenic trioxide for the first 5 days of every month, followed by oral itraconazole at 200 mg b.i.d. on days 6-28. Three patients completed three such cycles, while two discontinued early because of progressive disease or adverse events including a grade 3 infection and grade 2 transaminitis. All three patients who completed three treatment cycles achieved stable disease. The Stanford investigators speculated that concurrent continuous dosing might be required to obtain tumor shrinkage (JAMA Dermatol. 2016 Apr;152[4]:452-6).

Lots more work remains to be done in order to optimize combination therapy utilizing oral itraconazole for advanced BCC. Different dosing regimens and combinations of hedgehog pathway inhibitors need to be studied. Another important question is how effective itraconazole-based combinations will be in vismodegib-naive as compared with vismodegib-resistant patients, Dr. Leitenberger observed.

He reported having no financial conflicts regarding his presentation.

bjancin@mdedge.com

CHICAGO – Oral itraconazole shows potential for treatment of locally advanced or metastatic basal cell carcinoma (BCC) as well as Gorlin syndrome, Justin J. Leitenberger, MD, declared at the annual meeting of the American College of Mohs Surgery.

Bruce Jancin/MDedge News

The oral antifungal inhibits the hedgehog signaling pathway, a key driver of BCC. And while itraconazole is not as potent an inhibitor of hedgehog pathway expression as, say vismodegib (Erivedge), the antifungal acts at a separate site on the pathway, making it an attractive candidate for combination therapy, explained Dr. Leitenberger of Oregon Health & Science University, Portland.

Dermatologists at Stanford University have led the way in exploring oral itraconazole as a treatment for BCC. Among a series of 29 patients with one or more large but nonadvanced BCCs, 19 were treated using oral itraconazole at 200 mg b.i.d. for 1 month or 100 mg b.i.d. for an average of 2.3 months. Hedgehog pathway expression was reduced by 65% in the itraconazole-treated patients, as compared with the 90% reduction which is achieved with vismodegib.

Of more direct clinical relevance, however, itraconazole also reduced tumor area by 24%. Four of eight patients with 57 tumors achieved a partial response, and the other four had stable disease (J Clin Oncol. 2014 Mar 10;32[8]:745-51).

The Stanford group has also shown that combination therapy with oral itraconazole and intravenous arsenic trioxide reduces hedgehog pathway expression by 75%, up by an absolute 10% from itraconazole alone. The two agents inhibit the pathway at different sites.

Five patients with metastatic BCC who relapsed after treatment with vismodegib received intravenous arsenic trioxide for the first 5 days of every month, followed by oral itraconazole at 200 mg b.i.d. on days 6-28. Three patients completed three such cycles, while two discontinued early because of progressive disease or adverse events including a grade 3 infection and grade 2 transaminitis. All three patients who completed three treatment cycles achieved stable disease. The Stanford investigators speculated that concurrent continuous dosing might be required to obtain tumor shrinkage (JAMA Dermatol. 2016 Apr;152[4]:452-6).

Lots more work remains to be done in order to optimize combination therapy utilizing oral itraconazole for advanced BCC. Different dosing regimens and combinations of hedgehog pathway inhibitors need to be studied. Another important question is how effective itraconazole-based combinations will be in vismodegib-naive as compared with vismodegib-resistant patients, Dr. Leitenberger observed.

He reported having no financial conflicts regarding his presentation.

bjancin@mdedge.com

Mycosis fungoides (MF) is the most common type of cutaneous T-cell lymphoma (CTCL). MF is a rare disorder with an unclear etiology. Some have postulated an infectious agent as the cause. Atopic dermatitis may confer an increased risk because of the chronic stimulation of T cells. Males are more commonly affected than females by a 2:1 ratio. A worse prognosis is associated with advanced age. Children and adolescents may be affected as well.

With mycosis fungoides, there are three main types of skin lesions: patch, plaque, and tumor. Patients will progress from patch to plaque to tumor stage in classic MF. Often, lesions begin as scaly, erythematous patches that resemble eczema. Because of the nonspecific nature of early lesions, the median duration from the onset of skin lesions to the diagnosis of MF is 4-6 years. Patch stage lesions may be pruritic or asymptomatic. Commonly, they present in non–sun-exposed areas, such as the buttocks. Annular, infiltrated, red-brown or violaceous plaques can develop, which represent malignant T-cell infiltration. Many patients never progress past the plaque stage. Tumor stage MF is more aggressive, with nodules that may undergo necrosis and ulceration.

The leukemic form of MF is Sézary syndrome. Patients present with pruritic erythroderma and lymphadenopathy. Nail dystrophy, scaling of palms and soles, and alopecia may be present. A peripheral blood smear reveals Sézary cells, which are large, hyperconvoluted lymphocytes. The count of Sézary cells is usually greater than 1000 cells/mm³.

Histology of early lesions may not be diagnostic for CTCL. Often, biopsies will be read as eczematous or psoriasiform for years before the diagnosis of MF is made. Classically, epidermotropism (single-cell exocytosis of lymphocytes into the epidermis) is present. Advanced stages may show a dense infiltrate of lymphocytes in the dermis. Groups of lymphocytes in the epidermis form Pautrier’s microabscesses. Mycosis cells may exhibit cerebriform nuclei. Neoplastic cells in MF are CD3+, CD4+, CD45RO+, CD8–. Tissue can be sent for T-cell gene rearrangement polymerase chain reaction. The presence of monoclonal T-cell gene receptor rearrangements can aid in the diagnosis of MF.

Treatment includes topical steroids, mechlorethamine (nitrogen mustard) or bexarotene gel, PUVA therapy, and narrow-band UVB light for limited and/or patch disease. Localized radiotherapy can be used for more resistant lesions. Topical therapies are preferred in the early stages in MF. Systemic treatments for patients who do not respond to local therapy, or in more advanced disease include methotrexate, interferon-alpha, oral bexarotene, denileukin diftitox, and combination chemotherapy. Photopheresis is reserved for erythrodermic disease.

This case and photo were submitted by Dr. Bilu Martin.

Dr. Bilu Martin is a board-certified dermatologist in private practice in Aventura, Fla. More diagnostic cases are available at edermatologynews.com. To submit a case for possible publication, send an email to dermnews@mdedge.com.

Mycosis fungoides (MF) is the most common type of cutaneous T-cell lymphoma (CTCL). MF is a rare disorder with an unclear etiology. Some have postulated an infectious agent as the cause. Atopic dermatitis may confer an increased risk because of the chronic stimulation of T cells. Males are more commonly affected than females by a 2:1 ratio. A worse prognosis is associated with advanced age. Children and adolescents may be affected as well.

With mycosis fungoides, there are three main types of skin lesions: patch, plaque, and tumor. Patients will progress from patch to plaque to tumor stage in classic MF. Often, lesions begin as scaly, erythematous patches that resemble eczema. Because of the nonspecific nature of early lesions, the median duration from the onset of skin lesions to the diagnosis of MF is 4-6 years. Patch stage lesions may be pruritic or asymptomatic. Commonly, they present in non–sun-exposed areas, such as the buttocks. Annular, infiltrated, red-brown or violaceous plaques can develop, which represent malignant T-cell infiltration. Many patients never progress past the plaque stage. Tumor stage MF is more aggressive, with nodules that may undergo necrosis and ulceration.

The leukemic form of MF is Sézary syndrome. Patients present with pruritic erythroderma and lymphadenopathy. Nail dystrophy, scaling of palms and soles, and alopecia may be present. A peripheral blood smear reveals Sézary cells, which are large, hyperconvoluted lymphocytes. The count of Sézary cells is usually greater than 1000 cells/mm³.

Histology of early lesions may not be diagnostic for CTCL. Often, biopsies will be read as eczematous or psoriasiform for years before the diagnosis of MF is made. Classically, epidermotropism (single-cell exocytosis of lymphocytes into the epidermis) is present. Advanced stages may show a dense infiltrate of lymphocytes in the dermis. Groups of lymphocytes in the epidermis form Pautrier’s microabscesses. Mycosis cells may exhibit cerebriform nuclei. Neoplastic cells in MF are CD3+, CD4+, CD45RO+, CD8–. Tissue can be sent for T-cell gene rearrangement polymerase chain reaction. The presence of monoclonal T-cell gene receptor rearrangements can aid in the diagnosis of MF.

Treatment includes topical steroids, mechlorethamine (nitrogen mustard) or bexarotene gel, PUVA therapy, and narrow-band UVB light for limited and/or patch disease. Localized radiotherapy can be used for more resistant lesions. Topical therapies are preferred in the early stages in MF. Systemic treatments for patients who do not respond to local therapy, or in more advanced disease include methotrexate, interferon-alpha, oral bexarotene, denileukin diftitox, and combination chemotherapy. Photopheresis is reserved for erythrodermic disease.

This case and photo were submitted by Dr. Bilu Martin.

Dr. Bilu Martin is a board-certified dermatologist in private practice in Aventura, Fla. More diagnostic cases are available at edermatologynews.com. To submit a case for possible publication, send an email to dermnews@mdedge.com.

Mycosis fungoides (MF) is the most common type of cutaneous T-cell lymphoma (CTCL). MF is a rare disorder with an unclear etiology. Some have postulated an infectious agent as the cause. Atopic dermatitis may confer an increased risk because of the chronic stimulation of T cells. Males are more commonly affected than females by a 2:1 ratio. A worse prognosis is associated with advanced age. Children and adolescents may be affected as well.

With mycosis fungoides, there are three main types of skin lesions: patch, plaque, and tumor. Patients will progress from patch to plaque to tumor stage in classic MF. Often, lesions begin as scaly, erythematous patches that resemble eczema. Because of the nonspecific nature of early lesions, the median duration from the onset of skin lesions to the diagnosis of MF is 4-6 years. Patch stage lesions may be pruritic or asymptomatic. Commonly, they present in non–sun-exposed areas, such as the buttocks. Annular, infiltrated, red-brown or violaceous plaques can develop, which represent malignant T-cell infiltration. Many patients never progress past the plaque stage. Tumor stage MF is more aggressive, with nodules that may undergo necrosis and ulceration.

The leukemic form of MF is Sézary syndrome. Patients present with pruritic erythroderma and lymphadenopathy. Nail dystrophy, scaling of palms and soles, and alopecia may be present. A peripheral blood smear reveals Sézary cells, which are large, hyperconvoluted lymphocytes. The count of Sézary cells is usually greater than 1000 cells/mm³.

Histology of early lesions may not be diagnostic for CTCL. Often, biopsies will be read as eczematous or psoriasiform for years before the diagnosis of MF is made. Classically, epidermotropism (single-cell exocytosis of lymphocytes into the epidermis) is present. Advanced stages may show a dense infiltrate of lymphocytes in the dermis. Groups of lymphocytes in the epidermis form Pautrier’s microabscesses. Mycosis cells may exhibit cerebriform nuclei. Neoplastic cells in MF are CD3+, CD4+, CD45RO+, CD8–. Tissue can be sent for T-cell gene rearrangement polymerase chain reaction. The presence of monoclonal T-cell gene receptor rearrangements can aid in the diagnosis of MF.

Treatment includes topical steroids, mechlorethamine (nitrogen mustard) or bexarotene gel, PUVA therapy, and narrow-band UVB light for limited and/or patch disease. Localized radiotherapy can be used for more resistant lesions. Topical therapies are preferred in the early stages in MF. Systemic treatments for patients who do not respond to local therapy, or in more advanced disease include methotrexate, interferon-alpha, oral bexarotene, denileukin diftitox, and combination chemotherapy. Photopheresis is reserved for erythrodermic disease.

This case and photo were submitted by Dr. Bilu Martin.

Dr. Bilu Martin is a board-certified dermatologist in private practice in Aventura, Fla. More diagnostic cases are available at edermatologynews.com. To submit a case for possible publication, send an email to dermnews@mdedge.com.

For patients with locally advanced or metastatic basal cell carcinoma, Sonic hedgehog inhibitors (SSHi) are effective but are associated with primarily partial responses, and the two Food and Drug Administration–approved agents have significant toxicities, results of a systematic review and meta-analysis indicated.

Data on patients with metastatic or locally advanced basal cell carcinoma (BCC) treated with either vismodegib (Erivedge) or sonidegib (Odomzo) showed that the two agents had roughly similar overall response rates (ORR). Vismodegib, however, had a significantly higher rate of complete responses (CR) in patients with locally advanced disease, reported Pingxing Xie, MD, PhD, and Philippe Lefrançois, MD, PhD, from McGill University, Montreal.

“Common side effects of SHHi therapy tend to incapacitate patients, leading to high discontinuation rates. Over 25% of patients stopped treatment due to side effects. Most side effects are reversible after therapy cessation, except cases of persistent alopecia have been reported,” they wrote in the Journal of the American Academy of Dermatology.

The authors conducted the review to evaluate SHHi as a class and to get a better idea of the efficacy and safety of each agent in the class. They searched the literature to identify all studies using SHHi to treat BCC with vismodegib, sonidegib, itraconazole, or the investigational compound TAK-441, and identified 14 studies focused on vismodegib, 2 on sonidegib, and 1 each on itraconazole and TAK-441.

Of the 18 studies, data from 16 were pooled in fixed-effects linear models to analyze efficacy. The pooled ORR for all patients was 59.6%, “indicating that most patients receiving SHHi achieve at least a partial response.”

Combined ORR results showed a rate of 61.9% for vismodegib, 55.2% for sonidegib, 50% for itraconazole, and 20% for TAK-441, although data for the latter two agents were limited.

In studies looking at locally advanced and metastatic BCC separately, vismodegib was numerically better but statistically similar to sonidegib for locally advanced disease (ORR, 68.8% vs. 56.6%). However, vismodegib was significantly superior to sonidegib for patients with metastatic BCC (ORR, 39.7% vs. 14.7%; P = .007).

The pooled CR for all patients was 23.5%, and there were no CRs with either itraconazole or TAK-441. The combined CR rate for vismodegib was 28% (P = .012). The combined CR rate for sonidegib was just 8.9% and was not statistically significant, the investigators found.

In subgroup analyses for locally advanced BCC, the CR rate for vismodegib was 30.9% for vismodegib (P = .012), “meaning that many patients can expect cure.” In contrast, only 3% of patients treated for locally advanced disease had a CR with sonidegib. The difference between the drugs in this subpopulation was significant (P less than .0001).

Neither drug produced significant CRs in patients with metastatic melanoma, and the pooled clinical benefit rate (all patients with stable disease or better) was 94.9%, with rates similar among all four drugs.

Pooled prevalences of adverse events showed a 67.1% prevalence of muscle spasms, 54.1% prevalence of dysgeusia, and a 57.7% prevalence of alopecia. The proportions of side effects were similar between vismodegib and sonidegib, but sonidegib was associated with a higher prevalence of upper gastrointestinal tract distress than vismodegib.

The study was partially funded by the Canadian Dermatology Foundation. The authors reported having no conflicts of interest.

SOURCE: Xie P et al. J Am Acad Dermatol. 2018 Jul 9. doi: 10.1016/j.jaad.2018.07.004.

For patients with locally advanced or metastatic basal cell carcinoma, Sonic hedgehog inhibitors (SSHi) are effective but are associated with primarily partial responses, and the two Food and Drug Administration–approved agents have significant toxicities, results of a systematic review and meta-analysis indicated.

Data on patients with metastatic or locally advanced basal cell carcinoma (BCC) treated with either vismodegib (Erivedge) or sonidegib (Odomzo) showed that the two agents had roughly similar overall response rates (ORR). Vismodegib, however, had a significantly higher rate of complete responses (CR) in patients with locally advanced disease, reported Pingxing Xie, MD, PhD, and Philippe Lefrançois, MD, PhD, from McGill University, Montreal.

“Common side effects of SHHi therapy tend to incapacitate patients, leading to high discontinuation rates. Over 25% of patients stopped treatment due to side effects. Most side effects are reversible after therapy cessation, except cases of persistent alopecia have been reported,” they wrote in the Journal of the American Academy of Dermatology.

The authors conducted the review to evaluate SHHi as a class and to get a better idea of the efficacy and safety of each agent in the class. They searched the literature to identify all studies using SHHi to treat BCC with vismodegib, sonidegib, itraconazole, or the investigational compound TAK-441, and identified 14 studies focused on vismodegib, 2 on sonidegib, and 1 each on itraconazole and TAK-441.

Of the 18 studies, data from 16 were pooled in fixed-effects linear models to analyze efficacy. The pooled ORR for all patients was 59.6%, “indicating that most patients receiving SHHi achieve at least a partial response.”

Combined ORR results showed a rate of 61.9% for vismodegib, 55.2% for sonidegib, 50% for itraconazole, and 20% for TAK-441, although data for the latter two agents were limited.

In studies looking at locally advanced and metastatic BCC separately, vismodegib was numerically better but statistically similar to sonidegib for locally advanced disease (ORR, 68.8% vs. 56.6%). However, vismodegib was significantly superior to sonidegib for patients with metastatic BCC (ORR, 39.7% vs. 14.7%; P = .007).

The pooled CR for all patients was 23.5%, and there were no CRs with either itraconazole or TAK-441. The combined CR rate for vismodegib was 28% (P = .012). The combined CR rate for sonidegib was just 8.9% and was not statistically significant, the investigators found.

In subgroup analyses for locally advanced BCC, the CR rate for vismodegib was 30.9% for vismodegib (P = .012), “meaning that many patients can expect cure.” In contrast, only 3% of patients treated for locally advanced disease had a CR with sonidegib. The difference between the drugs in this subpopulation was significant (P less than .0001).

Neither drug produced significant CRs in patients with metastatic melanoma, and the pooled clinical benefit rate (all patients with stable disease or better) was 94.9%, with rates similar among all four drugs.

Pooled prevalences of adverse events showed a 67.1% prevalence of muscle spasms, 54.1% prevalence of dysgeusia, and a 57.7% prevalence of alopecia. The proportions of side effects were similar between vismodegib and sonidegib, but sonidegib was associated with a higher prevalence of upper gastrointestinal tract distress than vismodegib.

The study was partially funded by the Canadian Dermatology Foundation. The authors reported having no conflicts of interest.

SOURCE: Xie P et al. J Am Acad Dermatol. 2018 Jul 9. doi: 10.1016/j.jaad.2018.07.004.

For patients with locally advanced or metastatic basal cell carcinoma, Sonic hedgehog inhibitors (SSHi) are effective but are associated with primarily partial responses, and the two Food and Drug Administration–approved agents have significant toxicities, results of a systematic review and meta-analysis indicated.

Data on patients with metastatic or locally advanced basal cell carcinoma (BCC) treated with either vismodegib (Erivedge) or sonidegib (Odomzo) showed that the two agents had roughly similar overall response rates (ORR). Vismodegib, however, had a significantly higher rate of complete responses (CR) in patients with locally advanced disease, reported Pingxing Xie, MD, PhD, and Philippe Lefrançois, MD, PhD, from McGill University, Montreal.

“Common side effects of SHHi therapy tend to incapacitate patients, leading to high discontinuation rates. Over 25% of patients stopped treatment due to side effects. Most side effects are reversible after therapy cessation, except cases of persistent alopecia have been reported,” they wrote in the Journal of the American Academy of Dermatology.

The authors conducted the review to evaluate SHHi as a class and to get a better idea of the efficacy and safety of each agent in the class. They searched the literature to identify all studies using SHHi to treat BCC with vismodegib, sonidegib, itraconazole, or the investigational compound TAK-441, and identified 14 studies focused on vismodegib, 2 on sonidegib, and 1 each on itraconazole and TAK-441.

Of the 18 studies, data from 16 were pooled in fixed-effects linear models to analyze efficacy. The pooled ORR for all patients was 59.6%, “indicating that most patients receiving SHHi achieve at least a partial response.”

Combined ORR results showed a rate of 61.9% for vismodegib, 55.2% for sonidegib, 50% for itraconazole, and 20% for TAK-441, although data for the latter two agents were limited.

In studies looking at locally advanced and metastatic BCC separately, vismodegib was numerically better but statistically similar to sonidegib for locally advanced disease (ORR, 68.8% vs. 56.6%). However, vismodegib was significantly superior to sonidegib for patients with metastatic BCC (ORR, 39.7% vs. 14.7%; P = .007).

The pooled CR for all patients was 23.5%, and there were no CRs with either itraconazole or TAK-441. The combined CR rate for vismodegib was 28% (P = .012). The combined CR rate for sonidegib was just 8.9% and was not statistically significant, the investigators found.

In subgroup analyses for locally advanced BCC, the CR rate for vismodegib was 30.9% for vismodegib (P = .012), “meaning that many patients can expect cure.” In contrast, only 3% of patients treated for locally advanced disease had a CR with sonidegib. The difference between the drugs in this subpopulation was significant (P less than .0001).

Neither drug produced significant CRs in patients with metastatic melanoma, and the pooled clinical benefit rate (all patients with stable disease or better) was 94.9%, with rates similar among all four drugs.

Pooled prevalences of adverse events showed a 67.1% prevalence of muscle spasms, 54.1% prevalence of dysgeusia, and a 57.7% prevalence of alopecia. The proportions of side effects were similar between vismodegib and sonidegib, but sonidegib was associated with a higher prevalence of upper gastrointestinal tract distress than vismodegib.

The study was partially funded by the Canadian Dermatology Foundation. The authors reported having no conflicts of interest.

SOURCE: Xie P et al. J Am Acad Dermatol. 2018 Jul 9. doi: 10.1016/j.jaad.2018.07.004.

The Food and Drug Administration has approved mogamulizumab-kpkc (Poteligeo) for the treatment of adults with relapsed or refractory mycosis fungoides (MF) or Sézary syndrome (SS) who have received at least one prior systemic therapy.

Mogamulizumab is a humanized monoclonal antibody directed against CC chemokine receptor 4 (CCR4). It is the first biologic agent targeting CCR4 to be approved for patients in the United States.

Mogamulizumab is expected to be commercially available in the fourth quarter of 2018.

The FDA previously granted mogamulizumab breakthrough therapy and orphan drug designations, as well as priority review.

The approval is supported by the phase 3 MAVORIC trial. Results from this trial were presented at the 10th Annual T-cell Lymphoma Forum in February 2018.

MAVORIC enrolled 372 adults with histologically confirmed MF or SS who had failed at least one systemic therapy. They were randomized to receive mogamulizumab at 1.0 mg/kg (weekly for the first 4-week cycle and then every 2 weeks) or vorinostat at 400 mg daily. Patients were treated until disease progression or unacceptable toxicity. Those receiving vorinostat could cross over to mogamulizumab if they progressed or experienced intolerable toxicity. Baseline characteristics were similar between the treatment arms. The study’s primary endpoint was progression-free survival. The median progression-free survival was 7.7 months with mogamulizumab and 3.1 months with vorinostat (hazard ratio, 0.53; P less than .0001).

The global overall response rate was 28% (52/189) in the mogamulizumab arm and 5% (9/186) in the vorinostat arm (P less than .0001). For patients with MF, the ORR was 21% with mogamulizumab and 7% with vorinostat; for patients with SS, the ORR was 37% and 2%, respectively. After crossover, the ORR in the mogamulizumab arm was 30% (41/136).

The median duration of response (DOR) was 14 months in the mogamulizumab arm and 9 months in the vorinostat arm. For MF patients, the median DOR was 13 months with mogamulizumab and 9 months with vorinostat; for SS patients, the median DOR was 17 months and 7 months, respectively.

The most common treatment-emergent adverse events (AEs), which occurred in at least 20% of patients in either arm (mogamulizumab and vorinostat, respectively), included the following:

• Infusion-related reactions (33.2% vs. 0.5%).
• Drug eruptions (23.9% vs. 0.5%).
• Diarrhea (23.4% vs. 61.8%).
• Nausea (15.2% vs. 42.5%).
• Thrombocytopenia (11.4% vs. 30.6%).
• Dysgeusia (3.3% vs. 28.0%).
• Increased blood creatinine (3.3% vs. 28.0%).
• Decreased appetite (7.6% vs. 24.7%).

There were no grade 4 AEs in the mogamulizumab arm. Grade 3 AEs in mogamulizumab recipients included drug eruptions (n = 8), infusion-related reactions (n = 3), fatigue (n = 3), decreased appetite (n = 2), nausea (n = 1), pyrexia (n = 1), and diarrhea (n = 1).

The drug is marketed by Kyowa Kirin.

The Food and Drug Administration has approved mogamulizumab-kpkc (Poteligeo) for the treatment of adults with relapsed or refractory mycosis fungoides (MF) or Sézary syndrome (SS) who have received at least one prior systemic therapy.

Mogamulizumab is a humanized monoclonal antibody directed against CC chemokine receptor 4 (CCR4). It is the first biologic agent targeting CCR4 to be approved for patients in the United States.

Mogamulizumab is expected to be commercially available in the fourth quarter of 2018.

The FDA previously granted mogamulizumab breakthrough therapy and orphan drug designations, as well as priority review.

The approval is supported by the phase 3 MAVORIC trial. Results from this trial were presented at the 10th Annual T-cell Lymphoma Forum in February 2018.

MAVORIC enrolled 372 adults with histologically confirmed MF or SS who had failed at least one systemic therapy. They were randomized to receive mogamulizumab at 1.0 mg/kg (weekly for the first 4-week cycle and then every 2 weeks) or vorinostat at 400 mg daily. Patients were treated until disease progression or unacceptable toxicity. Those receiving vorinostat could cross over to mogamulizumab if they progressed or experienced intolerable toxicity. Baseline characteristics were similar between the treatment arms. The study’s primary endpoint was progression-free survival. The median progression-free survival was 7.7 months with mogamulizumab and 3.1 months with vorinostat (hazard ratio, 0.53; P less than .0001).

The global overall response rate was 28% (52/189) in the mogamulizumab arm and 5% (9/186) in the vorinostat arm (P less than .0001). For patients with MF, the ORR was 21% with mogamulizumab and 7% with vorinostat; for patients with SS, the ORR was 37% and 2%, respectively. After crossover, the ORR in the mogamulizumab arm was 30% (41/136).

The median duration of response (DOR) was 14 months in the mogamulizumab arm and 9 months in the vorinostat arm. For MF patients, the median DOR was 13 months with mogamulizumab and 9 months with vorinostat; for SS patients, the median DOR was 17 months and 7 months, respectively.

The most common treatment-emergent adverse events (AEs), which occurred in at least 20% of patients in either arm (mogamulizumab and vorinostat, respectively), included the following:

• Infusion-related reactions (33.2% vs. 0.5%).
• Drug eruptions (23.9% vs. 0.5%).
• Diarrhea (23.4% vs. 61.8%).
• Nausea (15.2% vs. 42.5%).
• Thrombocytopenia (11.4% vs. 30.6%).
• Dysgeusia (3.3% vs. 28.0%).
• Increased blood creatinine (3.3% vs. 28.0%).
• Decreased appetite (7.6% vs. 24.7%).

There were no grade 4 AEs in the mogamulizumab arm. Grade 3 AEs in mogamulizumab recipients included drug eruptions (n = 8), infusion-related reactions (n = 3), fatigue (n = 3), decreased appetite (n = 2), nausea (n = 1), pyrexia (n = 1), and diarrhea (n = 1).

The drug is marketed by Kyowa Kirin.

The Food and Drug Administration has approved mogamulizumab-kpkc (Poteligeo) for the treatment of adults with relapsed or refractory mycosis fungoides (MF) or Sézary syndrome (SS) who have received at least one prior systemic therapy.

Mogamulizumab is a humanized monoclonal antibody directed against CC chemokine receptor 4 (CCR4). It is the first biologic agent targeting CCR4 to be approved for patients in the United States.

Mogamulizumab is expected to be commercially available in the fourth quarter of 2018.

The FDA previously granted mogamulizumab breakthrough therapy and orphan drug designations, as well as priority review.

The approval is supported by the phase 3 MAVORIC trial. Results from this trial were presented at the 10th Annual T-cell Lymphoma Forum in February 2018.

MAVORIC enrolled 372 adults with histologically confirmed MF or SS who had failed at least one systemic therapy. They were randomized to receive mogamulizumab at 1.0 mg/kg (weekly for the first 4-week cycle and then every 2 weeks) or vorinostat at 400 mg daily. Patients were treated until disease progression or unacceptable toxicity. Those receiving vorinostat could cross over to mogamulizumab if they progressed or experienced intolerable toxicity. Baseline characteristics were similar between the treatment arms. The study’s primary endpoint was progression-free survival. The median progression-free survival was 7.7 months with mogamulizumab and 3.1 months with vorinostat (hazard ratio, 0.53; P less than .0001).

The global overall response rate was 28% (52/189) in the mogamulizumab arm and 5% (9/186) in the vorinostat arm (P less than .0001). For patients with MF, the ORR was 21% with mogamulizumab and 7% with vorinostat; for patients with SS, the ORR was 37% and 2%, respectively. After crossover, the ORR in the mogamulizumab arm was 30% (41/136).

The median duration of response (DOR) was 14 months in the mogamulizumab arm and 9 months in the vorinostat arm. For MF patients, the median DOR was 13 months with mogamulizumab and 9 months with vorinostat; for SS patients, the median DOR was 17 months and 7 months, respectively.

The most common treatment-emergent adverse events (AEs), which occurred in at least 20% of patients in either arm (mogamulizumab and vorinostat, respectively), included the following:

• Infusion-related reactions (33.2% vs. 0.5%).
• Drug eruptions (23.9% vs. 0.5%).
• Diarrhea (23.4% vs. 61.8%).
• Nausea (15.2% vs. 42.5%).
• Thrombocytopenia (11.4% vs. 30.6%).
• Dysgeusia (3.3% vs. 28.0%).
• Increased blood creatinine (3.3% vs. 28.0%).
• Decreased appetite (7.6% vs. 24.7%).

There were no grade 4 AEs in the mogamulizumab arm. Grade 3 AEs in mogamulizumab recipients included drug eruptions (n = 8), infusion-related reactions (n = 3), fatigue (n = 3), decreased appetite (n = 2), nausea (n = 1), pyrexia (n = 1), and diarrhea (n = 1).

The drug is marketed by Kyowa Kirin.

Dermoscopic examination has been proven to increase diagnostic accuracy and decrease unnecessary biopsies of both melanoma and nonmelanoma skin cancers.^1,2 Digital dermoscopy refers to acquiring and storing digital dermoscopic photographs via digital camera, smart image capture devices such as smartphones and tablets, or any other devices used for image acquisition. The stored images may then be used in a variety of ways, including sequential digital monitoring, teledermoscopy, and machine learning.

Sequential Digital Monitoring

Sequential digital dermoscopy imaging (SDDI) is the capture and storage of dermoscopic images of suspicious lesions that are then monitored over time for changes. Studies have shown that SDDI allows for early detection of melanomas and leads to a decrease in the number of unnecessary excisions.^3,4 A meta-analysis of SDDI found that the chance of detecting melanoma increased with the length of monitoring, which suggests that continued follow-up, especially in high-risk groups, is crucial.⁴

Teledermoscopy

Teledermatology (telederm) is on the rise in the United States, with the number of programs and consultations increasing yearly. One study showed a 48% increase in telederm programs in the last 5 years.⁵ Studies have shown the addition of digital dermoscopic images improved the diagnostic accuracy in telederm skin cancer screenings versus clinical images alone.^6,7

Telederm currently is practiced in 2 main models: live-interactive video consultation and storage of images for future consultation (store and forward). Medicare currently only reimburses live-interactive telederm for patients in nonmetropolitan areas and store-and-forward telederm pilot programs in Alaska and Hawaii; however, Medicaid does reimburse for store and forward in a handful of states.8 Similar to dermatoscope use during clinical examination, there currently is no additional reimbursement for teledermoscopy. Of note, a willingness-to-pay survey of 214 students from a southwestern university health center showed that participants were willing to pay an average (SD) of $55.27 ($39.11) out of pocket for a teledermoscopy/telederm evaluation, citing factors such as convenience.⁹

Direct-to-consumer telederm offers a new way for patients to receive care.¹⁰ Some dermatoscopes (eg, DermLite HÜD [3Gen], Molescope/Molescope II [Metaoptima Technology Inc]) currently are marketed directly to consumers along with telederm services to facilitate direct-to-patient teledermoscopy.^11,12

Machine Learning

Big data and machine learning has been hailed as the future of medicine and dermatology alike.¹³ Machine learning is a type of artificial intelligence that uses computational algorithms (eg, neural networks) that allow computer programs to automatically improve their accuracy (learn) by analyzing large data sets. In dermatology, machine learning has been most notably used to train computers to identify images of skin cancer by way of large image databases.^14-17 One algorithm, a convolutional neural network (CNN), made headlines in 2017 when it was able to identify dermoscopic and clinical images of skin cancer with comparable accuracy to a group of 21 dermatologists.¹⁴ In 2018, the International Skin Imaging Collaboration (ISIC) published results of a study of the diagnostic accuracy of 25 computer algorithms compared to 8 dermatologists using a set of 100 dermoscopic images of melanoma and benign nevi.¹⁵ Using the average sensitivity of the dermatologists (82%), the top fusion algorithm in the study had a sensitivity of 76% versus 59% for the dermatologists (P=.02). These results compared the mean sensitivity of the dermatologists, as some individual dermatologists outperformed the algorithm.¹⁵ More recently, another CNN was compared to 58 international dermatologists in the classification of a set of 100 dermoscopic images (20 melanoma and 80 melanocytic nevi).¹⁶ Using the mean sensitivity of the dermatologists (86.6%), the CNN had a specificity of 92.5% versus 71.3% for dermatologists (P<.01). In the second part of the study, the dermatologists were given some clinical information and close-up photographs of the lesions, which improved their average (SD) sensitivity and specificity to 88.9% (9.6%)(P=.19) and 75.7% (11.7%)(P<.05), respectively. When compared to the CNN at this higher sensitivity, the CNN still had a higher specificity than the dermatologists (82.5% vs 75.7% [P<.01]).¹⁶ However, in real-life clinical practice dermatologists perform better, not only because they can collect more in-person clinical information but also because humans gather more information during live examination than when they are interpreting close-up clinical and/or dermoscopic images. In a sense, we currently are limited to comparing data that is incommensurable.

Machine learning studies have other notable limitations, such as data sets that do not contain a full spectrum of skin lesions or less common lesions (eg, pigmented seborrheic keratoses, amelanotic melanomas) and variation in image databases used.^15,16 For machine algorithms to improve, they require access to high-quality and ideally standardized digital dermoscopic image databases. The ISIC and other organizations currently have databases specifically for this purpose, but more images are needed.¹⁸ As additional practitioners incorporate digital dermoscopy in their clinical practice, the potential for larger databases and more accurate algorithms becomes a possibility. 

Image Acquisition

Many devices are available for digital dermoscopic image acquisition, including dermatoscopes that attach to smartphones and/or digital cameras and all-in-one systems (eTable). The exact system employed will depend on the practitioner's requirements for price, portability, speed, image quality, and software. Digital single-lens reflex (DSLR) cameras boast the highest image quality, while video dermoscopy traditionally yields stored images with poor resolution.¹⁹ Macroscopic images obtained by other imaging devices, including spectral imaging devices and reflectance confocal microscopy, usually are yielded via video dermoscopy or a video camera to capture images; thus, stored images generally are not as high quality. 

Smartphones are increasingly used for clinical imaging in dermatology.²⁰ Although DSLR cameras still take the highest-quality images, current smartphone image quality is comparable to digital cameras.^21,22 Computational photography uses computer processing power to enhance image quality and may bring smartphone image quality closer to DSLR cameras.^22,23 Smartphones with newer dual-lens cameras have been reported to further improve image quality.²¹ Current smartphones have the option of enabling high-dynamic-range imaging, which combines multiple images taken with different exposures to create a single image with improved dynamic range of luminosity. It has been reported that high-dynamic-range imaging may even enhance dermoscopic features of more challenging hypopigmented skin cancers.²⁴

Standardizing Imaging

There has been a concerted effort to standardize digital dermatologic image acquisition.^25,26 Standardization promises to facilitate data analysis, improve collaboration, protect patient privacy, and improve patient care.^13,26,27 At the forefront of image standardization is the ISIC organization, which recently published its Delphi consensus guidelines on standards for lesion imaging, including dermoscopy.²⁶

The true holy grail of image standardization is the Digital Imaging and Communications in Medicine (DICOM) standard.^26-28 The DICOM is a comprehensive imaging standard for storage, annotation, transfer, and display of images, and it is most notable for its use in radiology. The DICOM also could be applied to new imaging modalities in dermatology (eg, optical coherence tomography, reflectance confocal microscopy). Past efforts to develop a DICOM standard for dermatology were undertaken by a working group that has since disbanded.²⁷ Work by the ISIC and many others will hopefully lead to adoption of the DICOM standard by dermatology at some point in the future. 

Protected Health Information

The Health Insurance Portability and Accountability Act (HIPAA) requires protected health information (PHI) to be stored in a secure manner with limited access that sufficiently protects identifiable patient information. Although dermoscopic images generally are deidentified, they often are stored alongside clinical photographs and data that contains PHI in clinical practice.

Image storage can take 2 forms: (1) physical local storage on internal and external hard drives or (2) remote storage (eg, cloud-based storage). Encryption is essential regardless of the method of storage. It is required by law that loss of nonencrypted PHI be reported to all potentially affected patients, the US Department of Health & Human Services, and local/state media depending on the number of patients affected. Loss of PHI can result in fines of up to $1.5 million.²⁹ On the contrary, loss of properly encrypted data would not be required to be reported.³⁰

As smart image acquisition devices begin to dominate the clinical setting, practitioners need to be vigilant in securing patient PHI. There are multiple applications (apps) that allow for secure encrypted digital dermoscopic image acquisition and storage on smartphones. Additionally, it is important to secure smartphones with complex passcodes (eg, a mix of special characters, numbers, uppercase and lowercase letters). Most dermatoscope manufacturers have apps for image acquisition and storage that can be tied into other platforms or storage systems (eg, DermLite app [3Gen], Handyscope [FotoFinder Systems GmbH], VEOS app [Canfield Scientific, Inc]).²⁸ Other options include syncing images with current electronic medical record technologies, transferring photographs to HIPAA-compliant cloud storage, or transferring photographs to an encrypted computer and/or external hard drive. Some tips for securing data based on HIPAA and other guidelines are listed in the Table.^30,31

Conclusion

The expansion of teledermoscopy alongside direct-to-patient services may create additional incentives for clinicians to incorporate digital dermoscopy into their practice. As more practitioners adopt digital dermoscopy, machine learning driven by technological advancements and larger image data sets could influence the future practice of dermatology. With the rise in digital dermoscopy by way of smartphones, additional steps must be taken to ensure patients' PHI is safeguarded. Digital dermoscopy is a dynamic field that will likely see continued growth in the coming years.

Dermoscopic examination has been proven to increase diagnostic accuracy and decrease unnecessary biopsies of both melanoma and nonmelanoma skin cancers.^1,2 Digital dermoscopy refers to acquiring and storing digital dermoscopic photographs via digital camera, smart image capture devices such as smartphones and tablets, or any other devices used for image acquisition. The stored images may then be used in a variety of ways, including sequential digital monitoring, teledermoscopy, and machine learning.

Sequential Digital Monitoring

Sequential digital dermoscopy imaging (SDDI) is the capture and storage of dermoscopic images of suspicious lesions that are then monitored over time for changes. Studies have shown that SDDI allows for early detection of melanomas and leads to a decrease in the number of unnecessary excisions.^3,4 A meta-analysis of SDDI found that the chance of detecting melanoma increased with the length of monitoring, which suggests that continued follow-up, especially in high-risk groups, is crucial.⁴

Teledermoscopy

Teledermatology (telederm) is on the rise in the United States, with the number of programs and consultations increasing yearly. One study showed a 48% increase in telederm programs in the last 5 years.⁵ Studies have shown the addition of digital dermoscopic images improved the diagnostic accuracy in telederm skin cancer screenings versus clinical images alone.^6,7

Telederm currently is practiced in 2 main models: live-interactive video consultation and storage of images for future consultation (store and forward). Medicare currently only reimburses live-interactive telederm for patients in nonmetropolitan areas and store-and-forward telederm pilot programs in Alaska and Hawaii; however, Medicaid does reimburse for store and forward in a handful of states.8 Similar to dermatoscope use during clinical examination, there currently is no additional reimbursement for teledermoscopy. Of note, a willingness-to-pay survey of 214 students from a southwestern university health center showed that participants were willing to pay an average (SD) of $55.27 ($39.11) out of pocket for a teledermoscopy/telederm evaluation, citing factors such as convenience.⁹

Direct-to-consumer telederm offers a new way for patients to receive care.¹⁰ Some dermatoscopes (eg, DermLite HÜD [3Gen], Molescope/Molescope II [Metaoptima Technology Inc]) currently are marketed directly to consumers along with telederm services to facilitate direct-to-patient teledermoscopy.^11,12

Machine Learning

Big data and machine learning has been hailed as the future of medicine and dermatology alike.¹³ Machine learning is a type of artificial intelligence that uses computational algorithms (eg, neural networks) that allow computer programs to automatically improve their accuracy (learn) by analyzing large data sets. In dermatology, machine learning has been most notably used to train computers to identify images of skin cancer by way of large image databases.^14-17 One algorithm, a convolutional neural network (CNN), made headlines in 2017 when it was able to identify dermoscopic and clinical images of skin cancer with comparable accuracy to a group of 21 dermatologists.¹⁴ In 2018, the International Skin Imaging Collaboration (ISIC) published results of a study of the diagnostic accuracy of 25 computer algorithms compared to 8 dermatologists using a set of 100 dermoscopic images of melanoma and benign nevi.¹⁵ Using the average sensitivity of the dermatologists (82%), the top fusion algorithm in the study had a sensitivity of 76% versus 59% for the dermatologists (P=.02). These results compared the mean sensitivity of the dermatologists, as some individual dermatologists outperformed the algorithm.¹⁵ More recently, another CNN was compared to 58 international dermatologists in the classification of a set of 100 dermoscopic images (20 melanoma and 80 melanocytic nevi).¹⁶ Using the mean sensitivity of the dermatologists (86.6%), the CNN had a specificity of 92.5% versus 71.3% for dermatologists (P<.01). In the second part of the study, the dermatologists were given some clinical information and close-up photographs of the lesions, which improved their average (SD) sensitivity and specificity to 88.9% (9.6%)(P=.19) and 75.7% (11.7%)(P<.05), respectively. When compared to the CNN at this higher sensitivity, the CNN still had a higher specificity than the dermatologists (82.5% vs 75.7% [P<.01]).¹⁶ However, in real-life clinical practice dermatologists perform better, not only because they can collect more in-person clinical information but also because humans gather more information during live examination than when they are interpreting close-up clinical and/or dermoscopic images. In a sense, we currently are limited to comparing data that is incommensurable.

Machine learning studies have other notable limitations, such as data sets that do not contain a full spectrum of skin lesions or less common lesions (eg, pigmented seborrheic keratoses, amelanotic melanomas) and variation in image databases used.^15,16 For machine algorithms to improve, they require access to high-quality and ideally standardized digital dermoscopic image databases. The ISIC and other organizations currently have databases specifically for this purpose, but more images are needed.¹⁸ As additional practitioners incorporate digital dermoscopy in their clinical practice, the potential for larger databases and more accurate algorithms becomes a possibility. 

Image Acquisition

Many devices are available for digital dermoscopic image acquisition, including dermatoscopes that attach to smartphones and/or digital cameras and all-in-one systems (eTable). The exact system employed will depend on the practitioner's requirements for price, portability, speed, image quality, and software. Digital single-lens reflex (DSLR) cameras boast the highest image quality, while video dermoscopy traditionally yields stored images with poor resolution.¹⁹ Macroscopic images obtained by other imaging devices, including spectral imaging devices and reflectance confocal microscopy, usually are yielded via video dermoscopy or a video camera to capture images; thus, stored images generally are not as high quality. 

Smartphones are increasingly used for clinical imaging in dermatology.²⁰ Although DSLR cameras still take the highest-quality images, current smartphone image quality is comparable to digital cameras.^21,22 Computational photography uses computer processing power to enhance image quality and may bring smartphone image quality closer to DSLR cameras.^22,23 Smartphones with newer dual-lens cameras have been reported to further improve image quality.²¹ Current smartphones have the option of enabling high-dynamic-range imaging, which combines multiple images taken with different exposures to create a single image with improved dynamic range of luminosity. It has been reported that high-dynamic-range imaging may even enhance dermoscopic features of more challenging hypopigmented skin cancers.²⁴

Standardizing Imaging

There has been a concerted effort to standardize digital dermatologic image acquisition.^25,26 Standardization promises to facilitate data analysis, improve collaboration, protect patient privacy, and improve patient care.^13,26,27 At the forefront of image standardization is the ISIC organization, which recently published its Delphi consensus guidelines on standards for lesion imaging, including dermoscopy.²⁶

The true holy grail of image standardization is the Digital Imaging and Communications in Medicine (DICOM) standard.^26-28 The DICOM is a comprehensive imaging standard for storage, annotation, transfer, and display of images, and it is most notable for its use in radiology. The DICOM also could be applied to new imaging modalities in dermatology (eg, optical coherence tomography, reflectance confocal microscopy). Past efforts to develop a DICOM standard for dermatology were undertaken by a working group that has since disbanded.²⁷ Work by the ISIC and many others will hopefully lead to adoption of the DICOM standard by dermatology at some point in the future. 

Protected Health Information

The Health Insurance Portability and Accountability Act (HIPAA) requires protected health information (PHI) to be stored in a secure manner with limited access that sufficiently protects identifiable patient information. Although dermoscopic images generally are deidentified, they often are stored alongside clinical photographs and data that contains PHI in clinical practice.

Image storage can take 2 forms: (1) physical local storage on internal and external hard drives or (2) remote storage (eg, cloud-based storage). Encryption is essential regardless of the method of storage. It is required by law that loss of nonencrypted PHI be reported to all potentially affected patients, the US Department of Health & Human Services, and local/state media depending on the number of patients affected. Loss of PHI can result in fines of up to $1.5 million.²⁹ On the contrary, loss of properly encrypted data would not be required to be reported.³⁰

As smart image acquisition devices begin to dominate the clinical setting, practitioners need to be vigilant in securing patient PHI. There are multiple applications (apps) that allow for secure encrypted digital dermoscopic image acquisition and storage on smartphones. Additionally, it is important to secure smartphones with complex passcodes (eg, a mix of special characters, numbers, uppercase and lowercase letters). Most dermatoscope manufacturers have apps for image acquisition and storage that can be tied into other platforms or storage systems (eg, DermLite app [3Gen], Handyscope [FotoFinder Systems GmbH], VEOS app [Canfield Scientific, Inc]).²⁸ Other options include syncing images with current electronic medical record technologies, transferring photographs to HIPAA-compliant cloud storage, or transferring photographs to an encrypted computer and/or external hard drive. Some tips for securing data based on HIPAA and other guidelines are listed in the Table.^30,31

Conclusion

The expansion of teledermoscopy alongside direct-to-patient services may create additional incentives for clinicians to incorporate digital dermoscopy into their practice. As more practitioners adopt digital dermoscopy, machine learning driven by technological advancements and larger image data sets could influence the future practice of dermatology. With the rise in digital dermoscopy by way of smartphones, additional steps must be taken to ensure patients' PHI is safeguarded. Digital dermoscopy is a dynamic field that will likely see continued growth in the coming years.

Dermoscopic examination has been proven to increase diagnostic accuracy and decrease unnecessary biopsies of both melanoma and nonmelanoma skin cancers.^1,2 Digital dermoscopy refers to acquiring and storing digital dermoscopic photographs via digital camera, smart image capture devices such as smartphones and tablets, or any other devices used for image acquisition. The stored images may then be used in a variety of ways, including sequential digital monitoring, teledermoscopy, and machine learning.

Sequential Digital Monitoring

Sequential digital dermoscopy imaging (SDDI) is the capture and storage of dermoscopic images of suspicious lesions that are then monitored over time for changes. Studies have shown that SDDI allows for early detection of melanomas and leads to a decrease in the number of unnecessary excisions.^3,4 A meta-analysis of SDDI found that the chance of detecting melanoma increased with the length of monitoring, which suggests that continued follow-up, especially in high-risk groups, is crucial.⁴

Teledermoscopy

Teledermatology (telederm) is on the rise in the United States, with the number of programs and consultations increasing yearly. One study showed a 48% increase in telederm programs in the last 5 years.⁵ Studies have shown the addition of digital dermoscopic images improved the diagnostic accuracy in telederm skin cancer screenings versus clinical images alone.^6,7

Telederm currently is practiced in 2 main models: live-interactive video consultation and storage of images for future consultation (store and forward). Medicare currently only reimburses live-interactive telederm for patients in nonmetropolitan areas and store-and-forward telederm pilot programs in Alaska and Hawaii; however, Medicaid does reimburse for store and forward in a handful of states.8 Similar to dermatoscope use during clinical examination, there currently is no additional reimbursement for teledermoscopy. Of note, a willingness-to-pay survey of 214 students from a southwestern university health center showed that participants were willing to pay an average (SD) of $55.27 ($39.11) out of pocket for a teledermoscopy/telederm evaluation, citing factors such as convenience.⁹

Direct-to-consumer telederm offers a new way for patients to receive care.¹⁰ Some dermatoscopes (eg, DermLite HÜD [3Gen], Molescope/Molescope II [Metaoptima Technology Inc]) currently are marketed directly to consumers along with telederm services to facilitate direct-to-patient teledermoscopy.^11,12

Machine Learning

Big data and machine learning has been hailed as the future of medicine and dermatology alike.¹³ Machine learning is a type of artificial intelligence that uses computational algorithms (eg, neural networks) that allow computer programs to automatically improve their accuracy (learn) by analyzing large data sets. In dermatology, machine learning has been most notably used to train computers to identify images of skin cancer by way of large image databases.^14-17 One algorithm, a convolutional neural network (CNN), made headlines in 2017 when it was able to identify dermoscopic and clinical images of skin cancer with comparable accuracy to a group of 21 dermatologists.¹⁴ In 2018, the International Skin Imaging Collaboration (ISIC) published results of a study of the diagnostic accuracy of 25 computer algorithms compared to 8 dermatologists using a set of 100 dermoscopic images of melanoma and benign nevi.¹⁵ Using the average sensitivity of the dermatologists (82%), the top fusion algorithm in the study had a sensitivity of 76% versus 59% for the dermatologists (P=.02). These results compared the mean sensitivity of the dermatologists, as some individual dermatologists outperformed the algorithm.¹⁵ More recently, another CNN was compared to 58 international dermatologists in the classification of a set of 100 dermoscopic images (20 melanoma and 80 melanocytic nevi).¹⁶ Using the mean sensitivity of the dermatologists (86.6%), the CNN had a specificity of 92.5% versus 71.3% for dermatologists (P<.01). In the second part of the study, the dermatologists were given some clinical information and close-up photographs of the lesions, which improved their average (SD) sensitivity and specificity to 88.9% (9.6%)(P=.19) and 75.7% (11.7%)(P<.05), respectively. When compared to the CNN at this higher sensitivity, the CNN still had a higher specificity than the dermatologists (82.5% vs 75.7% [P<.01]).¹⁶ However, in real-life clinical practice dermatologists perform better, not only because they can collect more in-person clinical information but also because humans gather more information during live examination than when they are interpreting close-up clinical and/or dermoscopic images. In a sense, we currently are limited to comparing data that is incommensurable.

Machine learning studies have other notable limitations, such as data sets that do not contain a full spectrum of skin lesions or less common lesions (eg, pigmented seborrheic keratoses, amelanotic melanomas) and variation in image databases used.^15,16 For machine algorithms to improve, they require access to high-quality and ideally standardized digital dermoscopic image databases. The ISIC and other organizations currently have databases specifically for this purpose, but more images are needed.¹⁸ As additional practitioners incorporate digital dermoscopy in their clinical practice, the potential for larger databases and more accurate algorithms becomes a possibility. 

Image Acquisition

Many devices are available for digital dermoscopic image acquisition, including dermatoscopes that attach to smartphones and/or digital cameras and all-in-one systems (eTable). The exact system employed will depend on the practitioner's requirements for price, portability, speed, image quality, and software. Digital single-lens reflex (DSLR) cameras boast the highest image quality, while video dermoscopy traditionally yields stored images with poor resolution.¹⁹ Macroscopic images obtained by other imaging devices, including spectral imaging devices and reflectance confocal microscopy, usually are yielded via video dermoscopy or a video camera to capture images; thus, stored images generally are not as high quality. 

Smartphones are increasingly used for clinical imaging in dermatology.²⁰ Although DSLR cameras still take the highest-quality images, current smartphone image quality is comparable to digital cameras.^21,22 Computational photography uses computer processing power to enhance image quality and may bring smartphone image quality closer to DSLR cameras.^22,23 Smartphones with newer dual-lens cameras have been reported to further improve image quality.²¹ Current smartphones have the option of enabling high-dynamic-range imaging, which combines multiple images taken with different exposures to create a single image with improved dynamic range of luminosity. It has been reported that high-dynamic-range imaging may even enhance dermoscopic features of more challenging hypopigmented skin cancers.²⁴

Standardizing Imaging

There has been a concerted effort to standardize digital dermatologic image acquisition.^25,26 Standardization promises to facilitate data analysis, improve collaboration, protect patient privacy, and improve patient care.^13,26,27 At the forefront of image standardization is the ISIC organization, which recently published its Delphi consensus guidelines on standards for lesion imaging, including dermoscopy.²⁶

The true holy grail of image standardization is the Digital Imaging and Communications in Medicine (DICOM) standard.^26-28 The DICOM is a comprehensive imaging standard for storage, annotation, transfer, and display of images, and it is most notable for its use in radiology. The DICOM also could be applied to new imaging modalities in dermatology (eg, optical coherence tomography, reflectance confocal microscopy). Past efforts to develop a DICOM standard for dermatology were undertaken by a working group that has since disbanded.²⁷ Work by the ISIC and many others will hopefully lead to adoption of the DICOM standard by dermatology at some point in the future. 

Protected Health Information

The Health Insurance Portability and Accountability Act (HIPAA) requires protected health information (PHI) to be stored in a secure manner with limited access that sufficiently protects identifiable patient information. Although dermoscopic images generally are deidentified, they often are stored alongside clinical photographs and data that contains PHI in clinical practice.

Image storage can take 2 forms: (1) physical local storage on internal and external hard drives or (2) remote storage (eg, cloud-based storage). Encryption is essential regardless of the method of storage. It is required by law that loss of nonencrypted PHI be reported to all potentially affected patients, the US Department of Health & Human Services, and local/state media depending on the number of patients affected. Loss of PHI can result in fines of up to $1.5 million.²⁹ On the contrary, loss of properly encrypted data would not be required to be reported.³⁰

As smart image acquisition devices begin to dominate the clinical setting, practitioners need to be vigilant in securing patient PHI. There are multiple applications (apps) that allow for secure encrypted digital dermoscopic image acquisition and storage on smartphones. Additionally, it is important to secure smartphones with complex passcodes (eg, a mix of special characters, numbers, uppercase and lowercase letters). Most dermatoscope manufacturers have apps for image acquisition and storage that can be tied into other platforms or storage systems (eg, DermLite app [3Gen], Handyscope [FotoFinder Systems GmbH], VEOS app [Canfield Scientific, Inc]).²⁸ Other options include syncing images with current electronic medical record technologies, transferring photographs to HIPAA-compliant cloud storage, or transferring photographs to an encrypted computer and/or external hard drive. Some tips for securing data based on HIPAA and other guidelines are listed in the Table.^30,31

Conclusion

The expansion of teledermoscopy alongside direct-to-patient services may create additional incentives for clinicians to incorporate digital dermoscopy into their practice. As more practitioners adopt digital dermoscopy, machine learning driven by technological advancements and larger image data sets could influence the future practice of dermatology. With the rise in digital dermoscopy by way of smartphones, additional steps must be taken to ensure patients' PHI is safeguarded. Digital dermoscopy is a dynamic field that will likely see continued growth in the coming years.

Almost half of the individuals diagnosed with melanoma in a free skin cancer screening program otherwise would not have gone to a doctor to have their skin examined, according to an analysis of the American Academy of Dermatology’s national skin cancer screening program, during 1986-2014.

Courtesy AAD

The SPOTme program, a national skin cancer screening and education program conducted by volunteer dermatologists, was launched in 1985. More than 2 million free screenings have been provided by the program in a “predominantly high-risk population, rendering important clinical diagnoses for hundreds of thousands of participants,” according to first authors Jean-Phillip Okhovat, MD, of Beth Israel Deaconess Medical Center, and Derek Beaulieu, MD, of Tufts University, both in Boston, and their colleagues.

The analysis was published online in the Journal of the American Academy of Dermatology on July 26.

Their study analyzed data on almost 2 million people screened through the program from 1986-2014. About 62% were women; 90% were white, about 2% were black, and almost 4% were Hispanic. Almost 80% had no regular dermatologist, almost 73% had not been screened previously, almost 45% had never had a skin cancer check, and 9% were uninsured. Almost 31% reported a mole that had recently change in size, color, or shape; almost 34% said they had a family history of skin cancer, and about 14% said they had a personal history of skin cancer.

Participants were asked about demographics and risk factors, although some questions changed from year to year (for example, in 2009 and 2010, participants were asked about melanoma risk factors, and from 1992 through 2010, participants were asked about their access to dermatologic care).

During 1991-2014 (which did not include data for 1995, 1996, and 2000, which were not available), the screening program resulted in 20,628 clinical melanoma diagnoses, 156,087 clinical dysplastic nevi diagnoses, 32,893 clinical squamous cell carcinoma diagnoses, and 129,848 clinical basal cell carcinoma diagnoses.

Of those clinically diagnosed with melanoma during 1992-2010, 83% said they did not have a regular dermatologist, 77% said they had not been screened previously, and 47% said they would not have seen a doctor for a skin exam if the SPOTme program had not been available.

Of those screened in 2009 and 2010 , 72% were considered at high risk for melanoma (older than age 65 years, having a history of sunburns, a family history of skin cancer, and/or more than 50 moles or unusual moles).

Among the other findings was that from 1992 to 2010, about 12% of those with a clinical melanoma diagnosis were not insured, which increased over time, from almost 11% during 1992-1999 to almost 16% during 2007-2010.

The “consistently high rates” of multiple skin cancer risk factors among those newly screened in the study are consistent with previously reported data, “suggesting that there is an untapped pool of at-risk Americans who have yet to be screened for skin cancer,” the authors wrote. “While the SPOTme program cannot be expected to meet the demands of this larger at-risk population, increased publicity and educational campaigns led by the AAD and assistance to primary care physicians in triaging of patients who should be seen by dermatologists could decrease the number of Americans who need to be screened,” they added.

Limitations of the study included the inability to confirm the clinical diagnoses with histopathology, and no data from the providers were available.

The authors had no disclosures. SPOTme, part of the AAD’s SPOT Skin Cancer initiative, is supported by a grant from Bristol-Myers Squibb.

emechcatie@mdedge.com

SOURCE: Okhovat JP et al. J Am Acad Dermatol. https://doi./org/10.1016.j.jaad.2018.05.1242.

Almost half of the individuals diagnosed with melanoma in a free skin cancer screening program otherwise would not have gone to a doctor to have their skin examined, according to an analysis of the American Academy of Dermatology’s national skin cancer screening program, during 1986-2014.

Courtesy AAD

The SPOTme program, a national skin cancer screening and education program conducted by volunteer dermatologists, was launched in 1985. More than 2 million free screenings have been provided by the program in a “predominantly high-risk population, rendering important clinical diagnoses for hundreds of thousands of participants,” according to first authors Jean-Phillip Okhovat, MD, of Beth Israel Deaconess Medical Center, and Derek Beaulieu, MD, of Tufts University, both in Boston, and their colleagues.

The analysis was published online in the Journal of the American Academy of Dermatology on July 26.

Their study analyzed data on almost 2 million people screened through the program from 1986-2014. About 62% were women; 90% were white, about 2% were black, and almost 4% were Hispanic. Almost 80% had no regular dermatologist, almost 73% had not been screened previously, almost 45% had never had a skin cancer check, and 9% were uninsured. Almost 31% reported a mole that had recently change in size, color, or shape; almost 34% said they had a family history of skin cancer, and about 14% said they had a personal history of skin cancer.

Participants were asked about demographics and risk factors, although some questions changed from year to year (for example, in 2009 and 2010, participants were asked about melanoma risk factors, and from 1992 through 2010, participants were asked about their access to dermatologic care).

During 1991-2014 (which did not include data for 1995, 1996, and 2000, which were not available), the screening program resulted in 20,628 clinical melanoma diagnoses, 156,087 clinical dysplastic nevi diagnoses, 32,893 clinical squamous cell carcinoma diagnoses, and 129,848 clinical basal cell carcinoma diagnoses.

Of those clinically diagnosed with melanoma during 1992-2010, 83% said they did not have a regular dermatologist, 77% said they had not been screened previously, and 47% said they would not have seen a doctor for a skin exam if the SPOTme program had not been available.

Of those screened in 2009 and 2010 , 72% were considered at high risk for melanoma (older than age 65 years, having a history of sunburns, a family history of skin cancer, and/or more than 50 moles or unusual moles).

Among the other findings was that from 1992 to 2010, about 12% of those with a clinical melanoma diagnosis were not insured, which increased over time, from almost 11% during 1992-1999 to almost 16% during 2007-2010.

The “consistently high rates” of multiple skin cancer risk factors among those newly screened in the study are consistent with previously reported data, “suggesting that there is an untapped pool of at-risk Americans who have yet to be screened for skin cancer,” the authors wrote. “While the SPOTme program cannot be expected to meet the demands of this larger at-risk population, increased publicity and educational campaigns led by the AAD and assistance to primary care physicians in triaging of patients who should be seen by dermatologists could decrease the number of Americans who need to be screened,” they added.

Limitations of the study included the inability to confirm the clinical diagnoses with histopathology, and no data from the providers were available.

The authors had no disclosures. SPOTme, part of the AAD’s SPOT Skin Cancer initiative, is supported by a grant from Bristol-Myers Squibb.

emechcatie@mdedge.com

SOURCE: Okhovat JP et al. J Am Acad Dermatol. https://doi./org/10.1016.j.jaad.2018.05.1242.

Almost half of the individuals diagnosed with melanoma in a free skin cancer screening program otherwise would not have gone to a doctor to have their skin examined, according to an analysis of the American Academy of Dermatology’s national skin cancer screening program, during 1986-2014.

Courtesy AAD

The SPOTme program, a national skin cancer screening and education program conducted by volunteer dermatologists, was launched in 1985. More than 2 million free screenings have been provided by the program in a “predominantly high-risk population, rendering important clinical diagnoses for hundreds of thousands of participants,” according to first authors Jean-Phillip Okhovat, MD, of Beth Israel Deaconess Medical Center, and Derek Beaulieu, MD, of Tufts University, both in Boston, and their colleagues.

The analysis was published online in the Journal of the American Academy of Dermatology on July 26.

Their study analyzed data on almost 2 million people screened through the program from 1986-2014. About 62% were women; 90% were white, about 2% were black, and almost 4% were Hispanic. Almost 80% had no regular dermatologist, almost 73% had not been screened previously, almost 45% had never had a skin cancer check, and 9% were uninsured. Almost 31% reported a mole that had recently change in size, color, or shape; almost 34% said they had a family history of skin cancer, and about 14% said they had a personal history of skin cancer.

Participants were asked about demographics and risk factors, although some questions changed from year to year (for example, in 2009 and 2010, participants were asked about melanoma risk factors, and from 1992 through 2010, participants were asked about their access to dermatologic care).

During 1991-2014 (which did not include data for 1995, 1996, and 2000, which were not available), the screening program resulted in 20,628 clinical melanoma diagnoses, 156,087 clinical dysplastic nevi diagnoses, 32,893 clinical squamous cell carcinoma diagnoses, and 129,848 clinical basal cell carcinoma diagnoses.

Of those clinically diagnosed with melanoma during 1992-2010, 83% said they did not have a regular dermatologist, 77% said they had not been screened previously, and 47% said they would not have seen a doctor for a skin exam if the SPOTme program had not been available.

Of those screened in 2009 and 2010 , 72% were considered at high risk for melanoma (older than age 65 years, having a history of sunburns, a family history of skin cancer, and/or more than 50 moles or unusual moles).

Among the other findings was that from 1992 to 2010, about 12% of those with a clinical melanoma diagnosis were not insured, which increased over time, from almost 11% during 1992-1999 to almost 16% during 2007-2010.

The “consistently high rates” of multiple skin cancer risk factors among those newly screened in the study are consistent with previously reported data, “suggesting that there is an untapped pool of at-risk Americans who have yet to be screened for skin cancer,” the authors wrote. “While the SPOTme program cannot be expected to meet the demands of this larger at-risk population, increased publicity and educational campaigns led by the AAD and assistance to primary care physicians in triaging of patients who should be seen by dermatologists could decrease the number of Americans who need to be screened,” they added.

Limitations of the study included the inability to confirm the clinical diagnoses with histopathology, and no data from the providers were available.

The authors had no disclosures. SPOTme, part of the AAD’s SPOT Skin Cancer initiative, is supported by a grant from Bristol-Myers Squibb.

emechcatie@mdedge.com

SOURCE: Okhovat JP et al. J Am Acad Dermatol. https://doi./org/10.1016.j.jaad.2018.05.1242.