Lindsey Collins, MD

The Diagnosis: Primary Cutaneous Carcinosarcoma

The immunohistochemical findings supported an epithelial component consistent with moderately differentiated squamous cell carcinoma (SCC) and a mesenchymal component with features consistent with a sarcoma. Consequently, the lesion was diagnosed as a primary cutaneous carcinosarcoma (PCCS).

Primary cutaneous carcinosarcoma is a rare biphasic neoplasm consisting of malignant epithelial (carcinoma) and mesenchymal (sarcoma) components.¹ Primary cutaneous carcinosarcomas are uncommon, poorly understood, primary cutaneous tumors.^2,3 Characteristic of this tumor, cytokeratins highlight the epithelial component while vimentin highlights the mesenchymal component.⁴ Histologically, the sarcomatous components of PCCS often are highly variable, with an absence of transitional areas within the epithelial component, which frequently resembles basal cell carcinoma and/ or SCC.^5-7 Primary cutaneous carcinosarcoma favors areas of chronic UV radiation exposure, particularly on the head and neck. Most tumors present with a slowly growing, polypoid, flesh-colored to erythematous nodule due to the infiltrative mesenchymal component.⁷ Primary cutaneous carcinosarcoma primarily is diagnosed in elderly patients, with the majority of cases diagnosed in the eighth or ninth decades of life (range, 32–98 years).^1,8 Men appear to be twice as likely to be diagnosed with a PCCS compared to women.¹ Primary cutaneous carcinosarcomas are recognized as aggressive tumors with a high propensity to metastasize and recur locally, necessitating early diagnosis and treatment.⁴ Accurate diagnosis of PCCSs can be challenging due to the biphasic nature of the neoplasm as well as poor differentiation or unequal proportions of the epithelial and mesenchymal components.⁵ Additionally, overlapping diagnostic criteria coupled with vague demarcation between soft-tissue sarcomas and distinct carcinomas also may contribute to a delay in diagnosis.⁹ Treatment is achieved surgically by complete wide resection, with no evidence to support the use of adjuvant or neoadjuvant external beam radiation therapy. Due to the small number of reported cases, no treatment recommendations currently exist.¹

Surgical management with wide local excision has been disappointing, with recurrence rates reported as high as 33%.⁶ Primary cutaneous carcinosarcoma has an estimated overall recurrence rate of 19% and a 5-year disease-free rate of 50%.¹⁰ Risk factors associated with poorer prognosis include tumors with adnexal subtype, age less than 65 years, rapid tumor growth, a tumor greater than 20 mm at presentation, and a long-standing tumor lasting up to 30 years.^2,4 Although wide local excision and Mohs micrographic surgery (MMS) both have been utilized successfully, MMS has been shown to result in a cure rate of greater than 98%.⁶

Atypical fibroxanthoma (AFX) is a cutaneous tumor of fibrohistiocytic mesenchymal origin that typically manifests on sun-damaged skin in elderly individuals. Clinically, it presents as a rapidly growing neoplasm that often ulcerates and bleeds. These heterogenous neoplasms have several distinct characteristics, including dense cellularity with disorganized, large, pleomorphic, and atypical-appearing spindle-shaped cells arising in the upper layers of the dermis, often disseminating into the reticular dermis and occasionally into the subcutaneous fat (Figure 1). The neoplastic cells often exhibit hyperchromic and irregular nuclei, multinucleated giant cells, and atypical mitotic figures. In most cases, negative immunohistochemical staining with SOX-10, S-100, cytokeratins, desmin, and caldesmon will allow pathologists to differentiate between AFX and other common tumors on the differential diagnosis, such as SCC, melanoma, and leiomyosarcoma. CD10 and procollagen type 1 are positive antigenic markers in AFX, but they are not specific. The standard treatment of AFX includes wide local excision or MMS for superior margin control.¹¹

Spindle cell SCC presents as a raised or exophytic nodule, often with spontaneous bleeding and central ulceration. It usually presents on sun-damaged skin or in individuals with a history of ionizing radiation. Histologically, it is characterized by atypical spindleshaped keratinocytes in the dermis existing as single cells or cohesive nests along with keratin pearls (Figure 2). The atypical spindle cells may comprise the entire tumor or only a small portion. The use of immunohistochemical markers often is required to establish a definitive diagnosis. Spindle cell SCC stains positively, albeit frequently focally, for p63, p40, and high-molecular-weight cytokeratins such as cytokeratin 5/6, while S-100 protein, SOX-10, MART-1/Melan-A, and muscle-specific actin stains typically are negative. Wide local excision or MMS is recommended for treatment of these lesions.¹²

Primary cutaneous myoepithelial carcinomas are uncommon neoplasms of myoepithelial differentiation. Clinically, they often arise as soft nodular lesions on the head, neck, and lower extremities with a bimodal age distribution (50 years). Histologically cutaneous myoepithelial tumors are well-differentiated, dermal-based nodules without connection to the overlying epidermis (Figure 3). The myoepithelial cells can exhibit spindled, epithelioid, plasmacytoid, or clear cell morphologic features and show variability in cell growth patterns. One of the most common growth patterns is oval to round cells forming cords and chains in a chondromyxoid stroma. Most cases display an immunophenotyped co-expression of an epithelial cytokeratin and S-100 protein. Myoepithelial markers also may be present, including keratins, smooth muscle actin, calponin, glial fibrillary acidic protein, p63, and desmin. Surgical removal with wide local excision or MMS is essential.¹³

Leiomyosarcoma (LMS) is a tumor that originates from smooth muscle and rarely develops in the dermis.¹⁴ Pleomorphic LMS is a morphologic variant of LMS that has a low propensity to metastasize but commonly exhibits local recurrence.¹⁵ Leiomyosarcoma can present in any age group but most commonly manifests in individuals aged 50 to 70 years. Clinically, LMS presents as a firm solitary nodule with a smooth pink surface or a more exophytic tumor with a reddish or brown color on the extensor surface of the lower limbs; it is less common on the scalp and face.¹⁴ Histologically, most cases of pleomorphic LMS show small foci of fascicles consisting of smooth muscle tumor cells in addition to cellular pleomorphism (Figure 4).¹⁵ Many of these cells demonstrate a clear perinuclear vacuole that generally is appreciated in neoplastic smooth muscle cells.¹⁴ Pleomorphic LMS typically stains positively for at least one smooth muscle marker including desmin, h-caldesmon, muscle-specific actin, α-smooth muscle actin, or smooth muscle myosin in the leiomyosarcomatous fascicular areas.¹⁶ Complete surgical excision is the treatment of choice, and the best results are obtained with MMS.¹⁴

The Diagnosis: Primary Cutaneous Carcinosarcoma

The immunohistochemical findings supported an epithelial component consistent with moderately differentiated squamous cell carcinoma (SCC) and a mesenchymal component with features consistent with a sarcoma. Consequently, the lesion was diagnosed as a primary cutaneous carcinosarcoma (PCCS).

Primary cutaneous carcinosarcoma is a rare biphasic neoplasm consisting of malignant epithelial (carcinoma) and mesenchymal (sarcoma) components.¹ Primary cutaneous carcinosarcomas are uncommon, poorly understood, primary cutaneous tumors.^2,3 Characteristic of this tumor, cytokeratins highlight the epithelial component while vimentin highlights the mesenchymal component.⁴ Histologically, the sarcomatous components of PCCS often are highly variable, with an absence of transitional areas within the epithelial component, which frequently resembles basal cell carcinoma and/ or SCC.^5-7 Primary cutaneous carcinosarcoma favors areas of chronic UV radiation exposure, particularly on the head and neck. Most tumors present with a slowly growing, polypoid, flesh-colored to erythematous nodule due to the infiltrative mesenchymal component.⁷ Primary cutaneous carcinosarcoma primarily is diagnosed in elderly patients, with the majority of cases diagnosed in the eighth or ninth decades of life (range, 32–98 years).^1,8 Men appear to be twice as likely to be diagnosed with a PCCS compared to women.¹ Primary cutaneous carcinosarcomas are recognized as aggressive tumors with a high propensity to metastasize and recur locally, necessitating early diagnosis and treatment.⁴ Accurate diagnosis of PCCSs can be challenging due to the biphasic nature of the neoplasm as well as poor differentiation or unequal proportions of the epithelial and mesenchymal components.⁵ Additionally, overlapping diagnostic criteria coupled with vague demarcation between soft-tissue sarcomas and distinct carcinomas also may contribute to a delay in diagnosis.⁹ Treatment is achieved surgically by complete wide resection, with no evidence to support the use of adjuvant or neoadjuvant external beam radiation therapy. Due to the small number of reported cases, no treatment recommendations currently exist.¹

Surgical management with wide local excision has been disappointing, with recurrence rates reported as high as 33%.⁶ Primary cutaneous carcinosarcoma has an estimated overall recurrence rate of 19% and a 5-year disease-free rate of 50%.¹⁰ Risk factors associated with poorer prognosis include tumors with adnexal subtype, age less than 65 years, rapid tumor growth, a tumor greater than 20 mm at presentation, and a long-standing tumor lasting up to 30 years.^2,4 Although wide local excision and Mohs micrographic surgery (MMS) both have been utilized successfully, MMS has been shown to result in a cure rate of greater than 98%.⁶

Atypical fibroxanthoma (AFX) is a cutaneous tumor of fibrohistiocytic mesenchymal origin that typically manifests on sun-damaged skin in elderly individuals. Clinically, it presents as a rapidly growing neoplasm that often ulcerates and bleeds. These heterogenous neoplasms have several distinct characteristics, including dense cellularity with disorganized, large, pleomorphic, and atypical-appearing spindle-shaped cells arising in the upper layers of the dermis, often disseminating into the reticular dermis and occasionally into the subcutaneous fat (Figure 1). The neoplastic cells often exhibit hyperchromic and irregular nuclei, multinucleated giant cells, and atypical mitotic figures. In most cases, negative immunohistochemical staining with SOX-10, S-100, cytokeratins, desmin, and caldesmon will allow pathologists to differentiate between AFX and other common tumors on the differential diagnosis, such as SCC, melanoma, and leiomyosarcoma. CD10 and procollagen type 1 are positive antigenic markers in AFX, but they are not specific. The standard treatment of AFX includes wide local excision or MMS for superior margin control.¹¹

Spindle cell SCC presents as a raised or exophytic nodule, often with spontaneous bleeding and central ulceration. It usually presents on sun-damaged skin or in individuals with a history of ionizing radiation. Histologically, it is characterized by atypical spindleshaped keratinocytes in the dermis existing as single cells or cohesive nests along with keratin pearls (Figure 2). The atypical spindle cells may comprise the entire tumor or only a small portion. The use of immunohistochemical markers often is required to establish a definitive diagnosis. Spindle cell SCC stains positively, albeit frequently focally, for p63, p40, and high-molecular-weight cytokeratins such as cytokeratin 5/6, while S-100 protein, SOX-10, MART-1/Melan-A, and muscle-specific actin stains typically are negative. Wide local excision or MMS is recommended for treatment of these lesions.¹²

Primary cutaneous myoepithelial carcinomas are uncommon neoplasms of myoepithelial differentiation. Clinically, they often arise as soft nodular lesions on the head, neck, and lower extremities with a bimodal age distribution (50 years). Histologically cutaneous myoepithelial tumors are well-differentiated, dermal-based nodules without connection to the overlying epidermis (Figure 3). The myoepithelial cells can exhibit spindled, epithelioid, plasmacytoid, or clear cell morphologic features and show variability in cell growth patterns. One of the most common growth patterns is oval to round cells forming cords and chains in a chondromyxoid stroma. Most cases display an immunophenotyped co-expression of an epithelial cytokeratin and S-100 protein. Myoepithelial markers also may be present, including keratins, smooth muscle actin, calponin, glial fibrillary acidic protein, p63, and desmin. Surgical removal with wide local excision or MMS is essential.¹³

Leiomyosarcoma (LMS) is a tumor that originates from smooth muscle and rarely develops in the dermis.¹⁴ Pleomorphic LMS is a morphologic variant of LMS that has a low propensity to metastasize but commonly exhibits local recurrence.¹⁵ Leiomyosarcoma can present in any age group but most commonly manifests in individuals aged 50 to 70 years. Clinically, LMS presents as a firm solitary nodule with a smooth pink surface or a more exophytic tumor with a reddish or brown color on the extensor surface of the lower limbs; it is less common on the scalp and face.¹⁴ Histologically, most cases of pleomorphic LMS show small foci of fascicles consisting of smooth muscle tumor cells in addition to cellular pleomorphism (Figure 4).¹⁵ Many of these cells demonstrate a clear perinuclear vacuole that generally is appreciated in neoplastic smooth muscle cells.¹⁴ Pleomorphic LMS typically stains positively for at least one smooth muscle marker including desmin, h-caldesmon, muscle-specific actin, α-smooth muscle actin, or smooth muscle myosin in the leiomyosarcomatous fascicular areas.¹⁶ Complete surgical excision is the treatment of choice, and the best results are obtained with MMS.¹⁴

The Diagnosis: Primary Cutaneous Carcinosarcoma

The immunohistochemical findings supported an epithelial component consistent with moderately differentiated squamous cell carcinoma (SCC) and a mesenchymal component with features consistent with a sarcoma. Consequently, the lesion was diagnosed as a primary cutaneous carcinosarcoma (PCCS).

Primary cutaneous carcinosarcoma is a rare biphasic neoplasm consisting of malignant epithelial (carcinoma) and mesenchymal (sarcoma) components.¹ Primary cutaneous carcinosarcomas are uncommon, poorly understood, primary cutaneous tumors.^2,3 Characteristic of this tumor, cytokeratins highlight the epithelial component while vimentin highlights the mesenchymal component.⁴ Histologically, the sarcomatous components of PCCS often are highly variable, with an absence of transitional areas within the epithelial component, which frequently resembles basal cell carcinoma and/ or SCC.^5-7 Primary cutaneous carcinosarcoma favors areas of chronic UV radiation exposure, particularly on the head and neck. Most tumors present with a slowly growing, polypoid, flesh-colored to erythematous nodule due to the infiltrative mesenchymal component.⁷ Primary cutaneous carcinosarcoma primarily is diagnosed in elderly patients, with the majority of cases diagnosed in the eighth or ninth decades of life (range, 32–98 years).^1,8 Men appear to be twice as likely to be diagnosed with a PCCS compared to women.¹ Primary cutaneous carcinosarcomas are recognized as aggressive tumors with a high propensity to metastasize and recur locally, necessitating early diagnosis and treatment.⁴ Accurate diagnosis of PCCSs can be challenging due to the biphasic nature of the neoplasm as well as poor differentiation or unequal proportions of the epithelial and mesenchymal components.⁵ Additionally, overlapping diagnostic criteria coupled with vague demarcation between soft-tissue sarcomas and distinct carcinomas also may contribute to a delay in diagnosis.⁹ Treatment is achieved surgically by complete wide resection, with no evidence to support the use of adjuvant or neoadjuvant external beam radiation therapy. Due to the small number of reported cases, no treatment recommendations currently exist.¹

Surgical management with wide local excision has been disappointing, with recurrence rates reported as high as 33%.⁶ Primary cutaneous carcinosarcoma has an estimated overall recurrence rate of 19% and a 5-year disease-free rate of 50%.¹⁰ Risk factors associated with poorer prognosis include tumors with adnexal subtype, age less than 65 years, rapid tumor growth, a tumor greater than 20 mm at presentation, and a long-standing tumor lasting up to 30 years.^2,4 Although wide local excision and Mohs micrographic surgery (MMS) both have been utilized successfully, MMS has been shown to result in a cure rate of greater than 98%.⁶

Atypical fibroxanthoma (AFX) is a cutaneous tumor of fibrohistiocytic mesenchymal origin that typically manifests on sun-damaged skin in elderly individuals. Clinically, it presents as a rapidly growing neoplasm that often ulcerates and bleeds. These heterogenous neoplasms have several distinct characteristics, including dense cellularity with disorganized, large, pleomorphic, and atypical-appearing spindle-shaped cells arising in the upper layers of the dermis, often disseminating into the reticular dermis and occasionally into the subcutaneous fat (Figure 1). The neoplastic cells often exhibit hyperchromic and irregular nuclei, multinucleated giant cells, and atypical mitotic figures. In most cases, negative immunohistochemical staining with SOX-10, S-100, cytokeratins, desmin, and caldesmon will allow pathologists to differentiate between AFX and other common tumors on the differential diagnosis, such as SCC, melanoma, and leiomyosarcoma. CD10 and procollagen type 1 are positive antigenic markers in AFX, but they are not specific. The standard treatment of AFX includes wide local excision or MMS for superior margin control.¹¹

Spindle cell SCC presents as a raised or exophytic nodule, often with spontaneous bleeding and central ulceration. It usually presents on sun-damaged skin or in individuals with a history of ionizing radiation. Histologically, it is characterized by atypical spindleshaped keratinocytes in the dermis existing as single cells or cohesive nests along with keratin pearls (Figure 2). The atypical spindle cells may comprise the entire tumor or only a small portion. The use of immunohistochemical markers often is required to establish a definitive diagnosis. Spindle cell SCC stains positively, albeit frequently focally, for p63, p40, and high-molecular-weight cytokeratins such as cytokeratin 5/6, while S-100 protein, SOX-10, MART-1/Melan-A, and muscle-specific actin stains typically are negative. Wide local excision or MMS is recommended for treatment of these lesions.¹²

Primary cutaneous myoepithelial carcinomas are uncommon neoplasms of myoepithelial differentiation. Clinically, they often arise as soft nodular lesions on the head, neck, and lower extremities with a bimodal age distribution (50 years). Histologically cutaneous myoepithelial tumors are well-differentiated, dermal-based nodules without connection to the overlying epidermis (Figure 3). The myoepithelial cells can exhibit spindled, epithelioid, plasmacytoid, or clear cell morphologic features and show variability in cell growth patterns. One of the most common growth patterns is oval to round cells forming cords and chains in a chondromyxoid stroma. Most cases display an immunophenotyped co-expression of an epithelial cytokeratin and S-100 protein. Myoepithelial markers also may be present, including keratins, smooth muscle actin, calponin, glial fibrillary acidic protein, p63, and desmin. Surgical removal with wide local excision or MMS is essential.¹³

Leiomyosarcoma (LMS) is a tumor that originates from smooth muscle and rarely develops in the dermis.¹⁴ Pleomorphic LMS is a morphologic variant of LMS that has a low propensity to metastasize but commonly exhibits local recurrence.¹⁵ Leiomyosarcoma can present in any age group but most commonly manifests in individuals aged 50 to 70 years. Clinically, LMS presents as a firm solitary nodule with a smooth pink surface or a more exophytic tumor with a reddish or brown color on the extensor surface of the lower limbs; it is less common on the scalp and face.¹⁴ Histologically, most cases of pleomorphic LMS show small foci of fascicles consisting of smooth muscle tumor cells in addition to cellular pleomorphism (Figure 4).¹⁵ Many of these cells demonstrate a clear perinuclear vacuole that generally is appreciated in neoplastic smooth muscle cells.¹⁴ Pleomorphic LMS typically stains positively for at least one smooth muscle marker including desmin, h-caldesmon, muscle-specific actin, α-smooth muscle actin, or smooth muscle myosin in the leiomyosarcomatous fascicular areas.¹⁶ Complete surgical excision is the treatment of choice, and the best results are obtained with MMS.¹⁴

Mohs micrographic surgery (MMS) entails multiple time-consuming surgical and histological examinations for each patient. As surgical stages are performed and histological sections are processed, an efficient communication method among providers, medical assistants, histotechnologists, and patients is necessary to avoid delays. To address these and other communication issues, providers have focused on ways to increase clinic efficiency and improve patient-reported outcomes by utilizing new or repurposed communication technologies in their Mohs practice. 

Prior reports have highlighted the utility of hands-free headsets that allow real-time communication among staff members as a means of increasing clinic efficiency and decreasing patient wait times.^1-4 These systems may mediate a more rapid turnover between stages by mitigating the need for surgeons and support staff to assemble within a designated workspace.^1,3,4 However, there is no single or standardized communication method that best suits all surgical suites and MMS practices. Our study aimed to identify the current communication strategies employed by Mohs surgeons and thereby ascertain which method(s) portend(s) the highest benefit in average daily time savings and provider-perceived patient satisfaction.

Materials and Methods

Survey Instrument
A new 10-question electronic survey was published on the SurveyMonkey website, and a link to the survey was provided in a quarterly email that originated from the American College of Mohs Surgery and was distributed to all 1735 active members. Responses were obtained from January 2019 to February 2019.

Statistical Analysis
A statistical analysis was done to determine any significant associations among the providers’ responses. P<.05 was used to determine statistical significance. A Cochran-Armitage test for trend was used to identify significant associations between the number of rooms and the communication systems that were used. Thus, 7 total tests—1 for each device (whiteboard, light system, flag system, wired intercom, wireless intercom, walkie-talkie, or headset)—were conducted. The Cochran-Armitage test also was used to determine whether the probability of using the device was affected by the number of stations/surgical rooms that were attended by the Mohs surgeons. To determine whether the communication devices used were associated with higher patient satisfaction, a χ² test was conducted for each device (7 total tests), testing the categories of using that device (yes/no) and patient satisfaction (yes/no). A Fisher exact test of independence was used in any case where the proportion for the device and patient satisfaction was 25% or higher. To determine whether the communication method was associated with increased time savings, 7 total Cochran-Armitage tests were conducted, 1 for each device. A logistic regression model was used to determine whether there was a significant association between the number of stations and the likelihood of reporting patient satisfaction.

Results

Eighty-eight surgeons responded to the survey, with a response rate of 5% (88/1735). A total of 55 surgeons completed the survey in its entirety and were included in the data analysis. The most commonly used communication mediums were whiteboards (29/55 [53%]), followed by a flag system (16/55 [29%]) and a light system (13/55 [24%]). Most Mohs surgeons (52/55 [95%]) used the communication media to communicate with their staff only, and 76% (42/55) of Mohs surgeons believed that their communication media contributed to higher patient satisfaction. Overall, 58% (32/55) of Mohs surgeons stated that their communication media saved more than 15 minutes (on average) per day. The use of a whiteboard and/or flag system was reported as the least efficient method, with average daily time savings of 13 minutes. With the introduction of newer technology (wired or wireless intercoms, headsets, walkie-talkies, or internal messaging systems such as Skype) to the whiteboard and/or flag system, the time savings increased by 10 minutes per day. Nearly 25% (14/55) of surgeons utilized more than 1 communication system.

As the number of stations in an MMS suite increased, the probability of using a whiteboard to track the progress of the cases decreased. There were no statistically significant associations identified between the number of stations and the use of other communication devices (ie, flag system, light system, wireless intercom, wired intercom, walkie-talkie, headset). The stratified percentages of the amount of time savings for each communication modality are presented in the Figure (whiteboards and headsets were excluded because they did not increase time savings). The use of a light system was the only communication modality found to be statistically associated with an increase in provider-reported time savings (P=.0482; Figure). In addition, our analysis did not show an improvement in provider-reported patient satisfaction with any of the current systems used in MMS clinics.

Comment

The process of transmitting information among the medical team during MMS is a complex interplay involving the relay of crucial information, with many opportunities for the introduction of distraction and error. Despite numerous improvements in the efficiency of the preparation of histological specimens and implementation of various time-saving and tissue-saving surgical interventions, relatively little attention has been given to address the sometimes chaotic and challenging process of organizing results from each stage of multiple patients in an MMS surgical suite.⁵

As demonstrated by our survey, incorporation of a light-based system into an MMS clinic may improve workplace efficiency by decreasing the redundant use of support staff and allowing Mohs surgeons to transition from one station to the next seamlessly. Light-based communication systems provide an immediate notification for support staff via color-coded and/or numerically coded indicators on input switches located outside and inside the examination/surgery rooms. The switch indicators can be depressed with minimal disruption from station to station, thereby foregoing the need to interrupt an ongoing excision or closure to convey the status of the case. These systems may then permit enhanced clinic and workflow efficiency, which may help to shorten patient wait times.

Conclusion

Our study supports the use of light-based communication systems in MMS suites to improve efficiency in the clinic. Based on our analysis, light-based communication methods were significantly associated with improved time savings (P=.0482). Our study did not show an improvement in provider-reported satisfaction with any of the current systems used in MMS clinics. We hope that this information will help guide providers in implementing new communication techniques to improve clinic efficiency. 



Acknowledgments
The authors would like to thank Ms. Kathy Kyler (Oklahoma City, Oklahoma) for her assistance in preparing this manuscript. Support for Dr. Chen and Mr. Stubblefield was provided through National Institutes of Health, National Institute of General Medical Sciences [Grant 2U54GM104938-06, PI Judith James].

Mohs micrographic surgery (MMS) entails multiple time-consuming surgical and histological examinations for each patient. As surgical stages are performed and histological sections are processed, an efficient communication method among providers, medical assistants, histotechnologists, and patients is necessary to avoid delays. To address these and other communication issues, providers have focused on ways to increase clinic efficiency and improve patient-reported outcomes by utilizing new or repurposed communication technologies in their Mohs practice. 

Prior reports have highlighted the utility of hands-free headsets that allow real-time communication among staff members as a means of increasing clinic efficiency and decreasing patient wait times.^1-4 These systems may mediate a more rapid turnover between stages by mitigating the need for surgeons and support staff to assemble within a designated workspace.^1,3,4 However, there is no single or standardized communication method that best suits all surgical suites and MMS practices. Our study aimed to identify the current communication strategies employed by Mohs surgeons and thereby ascertain which method(s) portend(s) the highest benefit in average daily time savings and provider-perceived patient satisfaction.

Materials and Methods

Survey Instrument
A new 10-question electronic survey was published on the SurveyMonkey website, and a link to the survey was provided in a quarterly email that originated from the American College of Mohs Surgery and was distributed to all 1735 active members. Responses were obtained from January 2019 to February 2019.

Statistical Analysis
A statistical analysis was done to determine any significant associations among the providers’ responses. P<.05 was used to determine statistical significance. A Cochran-Armitage test for trend was used to identify significant associations between the number of rooms and the communication systems that were used. Thus, 7 total tests—1 for each device (whiteboard, light system, flag system, wired intercom, wireless intercom, walkie-talkie, or headset)—were conducted. The Cochran-Armitage test also was used to determine whether the probability of using the device was affected by the number of stations/surgical rooms that were attended by the Mohs surgeons. To determine whether the communication devices used were associated with higher patient satisfaction, a χ² test was conducted for each device (7 total tests), testing the categories of using that device (yes/no) and patient satisfaction (yes/no). A Fisher exact test of independence was used in any case where the proportion for the device and patient satisfaction was 25% or higher. To determine whether the communication method was associated with increased time savings, 7 total Cochran-Armitage tests were conducted, 1 for each device. A logistic regression model was used to determine whether there was a significant association between the number of stations and the likelihood of reporting patient satisfaction.

Results

Eighty-eight surgeons responded to the survey, with a response rate of 5% (88/1735). A total of 55 surgeons completed the survey in its entirety and were included in the data analysis. The most commonly used communication mediums were whiteboards (29/55 [53%]), followed by a flag system (16/55 [29%]) and a light system (13/55 [24%]). Most Mohs surgeons (52/55 [95%]) used the communication media to communicate with their staff only, and 76% (42/55) of Mohs surgeons believed that their communication media contributed to higher patient satisfaction. Overall, 58% (32/55) of Mohs surgeons stated that their communication media saved more than 15 minutes (on average) per day. The use of a whiteboard and/or flag system was reported as the least efficient method, with average daily time savings of 13 minutes. With the introduction of newer technology (wired or wireless intercoms, headsets, walkie-talkies, or internal messaging systems such as Skype) to the whiteboard and/or flag system, the time savings increased by 10 minutes per day. Nearly 25% (14/55) of surgeons utilized more than 1 communication system.

As the number of stations in an MMS suite increased, the probability of using a whiteboard to track the progress of the cases decreased. There were no statistically significant associations identified between the number of stations and the use of other communication devices (ie, flag system, light system, wireless intercom, wired intercom, walkie-talkie, headset). The stratified percentages of the amount of time savings for each communication modality are presented in the Figure (whiteboards and headsets were excluded because they did not increase time savings). The use of a light system was the only communication modality found to be statistically associated with an increase in provider-reported time savings (P=.0482; Figure). In addition, our analysis did not show an improvement in provider-reported patient satisfaction with any of the current systems used in MMS clinics.

Comment

The process of transmitting information among the medical team during MMS is a complex interplay involving the relay of crucial information, with many opportunities for the introduction of distraction and error. Despite numerous improvements in the efficiency of the preparation of histological specimens and implementation of various time-saving and tissue-saving surgical interventions, relatively little attention has been given to address the sometimes chaotic and challenging process of organizing results from each stage of multiple patients in an MMS surgical suite.⁵

As demonstrated by our survey, incorporation of a light-based system into an MMS clinic may improve workplace efficiency by decreasing the redundant use of support staff and allowing Mohs surgeons to transition from one station to the next seamlessly. Light-based communication systems provide an immediate notification for support staff via color-coded and/or numerically coded indicators on input switches located outside and inside the examination/surgery rooms. The switch indicators can be depressed with minimal disruption from station to station, thereby foregoing the need to interrupt an ongoing excision or closure to convey the status of the case. These systems may then permit enhanced clinic and workflow efficiency, which may help to shorten patient wait times.

Conclusion

Our study supports the use of light-based communication systems in MMS suites to improve efficiency in the clinic. Based on our analysis, light-based communication methods were significantly associated with improved time savings (P=.0482). Our study did not show an improvement in provider-reported satisfaction with any of the current systems used in MMS clinics. We hope that this information will help guide providers in implementing new communication techniques to improve clinic efficiency. 



Acknowledgments
The authors would like to thank Ms. Kathy Kyler (Oklahoma City, Oklahoma) for her assistance in preparing this manuscript. Support for Dr. Chen and Mr. Stubblefield was provided through National Institutes of Health, National Institute of General Medical Sciences [Grant 2U54GM104938-06, PI Judith James].

Mohs micrographic surgery (MMS) entails multiple time-consuming surgical and histological examinations for each patient. As surgical stages are performed and histological sections are processed, an efficient communication method among providers, medical assistants, histotechnologists, and patients is necessary to avoid delays. To address these and other communication issues, providers have focused on ways to increase clinic efficiency and improve patient-reported outcomes by utilizing new or repurposed communication technologies in their Mohs practice. 

Prior reports have highlighted the utility of hands-free headsets that allow real-time communication among staff members as a means of increasing clinic efficiency and decreasing patient wait times.^1-4 These systems may mediate a more rapid turnover between stages by mitigating the need for surgeons and support staff to assemble within a designated workspace.^1,3,4 However, there is no single or standardized communication method that best suits all surgical suites and MMS practices. Our study aimed to identify the current communication strategies employed by Mohs surgeons and thereby ascertain which method(s) portend(s) the highest benefit in average daily time savings and provider-perceived patient satisfaction.

Materials and Methods

Survey Instrument
A new 10-question electronic survey was published on the SurveyMonkey website, and a link to the survey was provided in a quarterly email that originated from the American College of Mohs Surgery and was distributed to all 1735 active members. Responses were obtained from January 2019 to February 2019.

Statistical Analysis
A statistical analysis was done to determine any significant associations among the providers’ responses. P<.05 was used to determine statistical significance. A Cochran-Armitage test for trend was used to identify significant associations between the number of rooms and the communication systems that were used. Thus, 7 total tests—1 for each device (whiteboard, light system, flag system, wired intercom, wireless intercom, walkie-talkie, or headset)—were conducted. The Cochran-Armitage test also was used to determine whether the probability of using the device was affected by the number of stations/surgical rooms that were attended by the Mohs surgeons. To determine whether the communication devices used were associated with higher patient satisfaction, a χ² test was conducted for each device (7 total tests), testing the categories of using that device (yes/no) and patient satisfaction (yes/no). A Fisher exact test of independence was used in any case where the proportion for the device and patient satisfaction was 25% or higher. To determine whether the communication method was associated with increased time savings, 7 total Cochran-Armitage tests were conducted, 1 for each device. A logistic regression model was used to determine whether there was a significant association between the number of stations and the likelihood of reporting patient satisfaction.

Results

Eighty-eight surgeons responded to the survey, with a response rate of 5% (88/1735). A total of 55 surgeons completed the survey in its entirety and were included in the data analysis. The most commonly used communication mediums were whiteboards (29/55 [53%]), followed by a flag system (16/55 [29%]) and a light system (13/55 [24%]). Most Mohs surgeons (52/55 [95%]) used the communication media to communicate with their staff only, and 76% (42/55) of Mohs surgeons believed that their communication media contributed to higher patient satisfaction. Overall, 58% (32/55) of Mohs surgeons stated that their communication media saved more than 15 minutes (on average) per day. The use of a whiteboard and/or flag system was reported as the least efficient method, with average daily time savings of 13 minutes. With the introduction of newer technology (wired or wireless intercoms, headsets, walkie-talkies, or internal messaging systems such as Skype) to the whiteboard and/or flag system, the time savings increased by 10 minutes per day. Nearly 25% (14/55) of surgeons utilized more than 1 communication system.

As the number of stations in an MMS suite increased, the probability of using a whiteboard to track the progress of the cases decreased. There were no statistically significant associations identified between the number of stations and the use of other communication devices (ie, flag system, light system, wireless intercom, wired intercom, walkie-talkie, headset). The stratified percentages of the amount of time savings for each communication modality are presented in the Figure (whiteboards and headsets were excluded because they did not increase time savings). The use of a light system was the only communication modality found to be statistically associated with an increase in provider-reported time savings (P=.0482; Figure). In addition, our analysis did not show an improvement in provider-reported patient satisfaction with any of the current systems used in MMS clinics.

Comment

The process of transmitting information among the medical team during MMS is a complex interplay involving the relay of crucial information, with many opportunities for the introduction of distraction and error. Despite numerous improvements in the efficiency of the preparation of histological specimens and implementation of various time-saving and tissue-saving surgical interventions, relatively little attention has been given to address the sometimes chaotic and challenging process of organizing results from each stage of multiple patients in an MMS surgical suite.⁵

As demonstrated by our survey, incorporation of a light-based system into an MMS clinic may improve workplace efficiency by decreasing the redundant use of support staff and allowing Mohs surgeons to transition from one station to the next seamlessly. Light-based communication systems provide an immediate notification for support staff via color-coded and/or numerically coded indicators on input switches located outside and inside the examination/surgery rooms. The switch indicators can be depressed with minimal disruption from station to station, thereby foregoing the need to interrupt an ongoing excision or closure to convey the status of the case. These systems may then permit enhanced clinic and workflow efficiency, which may help to shorten patient wait times.

Conclusion

Our study supports the use of light-based communication systems in MMS suites to improve efficiency in the clinic. Based on our analysis, light-based communication methods were significantly associated with improved time savings (P=.0482). Our study did not show an improvement in provider-reported satisfaction with any of the current systems used in MMS clinics. We hope that this information will help guide providers in implementing new communication techniques to improve clinic efficiency. 



Acknowledgments
The authors would like to thank Ms. Kathy Kyler (Oklahoma City, Oklahoma) for her assistance in preparing this manuscript. Support for Dr. Chen and Mr. Stubblefield was provided through National Institutes of Health, National Institute of General Medical Sciences [Grant 2U54GM104938-06, PI Judith James].

The incidence of posttransplant malignancy among solid organ transplant recipients (SOTRs) is 10%; skin cancer, primarily nonmelanoma skin cancer (NMSC), constitutes 49.5% of all malignancies in this population.¹ The etiology of the increased risk of cutaneous malignancy in SOTR is multifactorial:

• The skin of SOTRs is photosensitive, compared to that of immunocompetent patients, thus predisposing SOTRs to carcinogenic damage resulting from exposure to UV light.²
• Immunosuppression plays a key role in increasing the risk of cutaneous malignancy by inhibiting the ability of the immune system to recognize and destroy tumor cells.³
• Human papillomavirus (HPV) can play a role in carcinogenesis by promoting molecular pathways to proliferation and survival of nascent tumor cells⁴;Times New Romanβ-HPV strains are disseminated ubiquitously in the skin of immunosuppressed patients.⁵
• Some medications administered after transplantation can be directly carcinogenic.

NMSC in SOTRs also differs qualitatively from NMSC in immunocompetent patients. Cutaneous squamous cell carcinoma (cSCC) (FIGUREs 1 and 2) is the most common skin cancer among SOTRs, whereas basal cell carcinoma (BCC) is the most common skin cancer in the general population.³ cSCC in the SOTR population tends to be more aggressive, with more rapid local invasion and an increased rate of both in-transit and distant metastases, leading to an increase in morbidity and mortality. Mortality of metastatic cSCC among SOTRs is approximately 50%, compared to 20% in an otherwise healthy population.^3,6-8

The problem is relevant to primary care

Screening. Because there is a demonstrated reduction in morbidity and mortality associated with early detection and treatment of NMSC, regular screening of skin is important in the SOTR population.⁹ A study in Ontario, Canada, from 1994 to 2012 and comprising 10,183 SOTRs, found that adherence to an annual skin check regimen for ≥ 75% of the observation period was associated with a 34% reduction in cutaneous BCC- and cSCC-­related morbidity or death (adjusted hazard ratio = 0.66; 95% CI, 0.48-0.92).¹⁰ Although routine follow-up with a dermatologist is recommended for SOTRs,^9,11-15 only 2.1% of patients in the Canadian study were fully adherent with annual skin examination, and 55% never visited a dermatologist.¹⁰ Consequently, primary care physicians can play a key role in skin cancer screening for SOTRs.

Education regarding the importance of protection from the sun is also an essential part of primary care. A 2018 study of SOTRs in Turkey demonstrated that¹⁶

• 46% expressed a lack of knowledge of the hazards of sun exposure
• 44% did not recall ever receiving medical advice regarding sun protection
• 89% did not wear sun-protective clothing
• 86% did not use sunscreen daily.

Multiple studies have demonstrated the positive effect that preventive education and attendance at a dermatology or skin cancer screening clinic can have on sun-protective behaviors among SOTRs.^9,16-18 In the Turkish study, 100% of patients who reported using sunscreen daily had been undergoing regular dermatologic examination.¹⁶

In this article, we review current management guidelines regarding the prevention and treatment of NMSC in SOTRs.

Recommendations for prevention

Screening skin exams (TABLE 1^{1,11,12,15,19-23}). Although definitive guidelines do not exist regarding the frequency of a screening skin exam for SOTRs, multiple frequency-­determining algorithms have been proposed.^11,12,15,19 The recommended frequency of a skin exam is based on history of skin cancer; for SOTRs, the most common recommendation¹⁹ is a full-body skin examination as follows:

• annually—when there is no history of skin cancer
• every 6 months—when there is a history of actinic keratoses (AKs; precancerous lesions that carry a risk of transforming into cSCC) or a single low-risk NMSC
• every 3 months—when there is a history of multiple NMSCs or a single high-risk NMSC
• every 1 to 3 months—when there is a history of metastatic disease.

Continue to: Other risk factors...

Other risk factors for NMSC to consider in SOTRs when determining an appropriate follow-up regimen include any of the following^{1,20,21,24-26}:

• male gender, fair skin, history of childhood sunburn, history of smoking
• lung or heart transplantation, history of episodes of transplant rejection, age ≥ 50 years at transplantation
• immunosuppression with calcineurin inhibitors, compared to mammalian target of rapamycin (mTOR) inhibitors
• immunosuppression with cyclosporine, compared to tacrolimus
• an immunosuppressive regimen with > 1 immunosuppressant or an increased degree of immunosuppression
• antithymocyte globulin within the first year posttransplantation.

Regular screening of skin is important in the solid organ transplant population.

Because the intensity of immunosuppression and individual immunosuppressants used affect the risk of NMSC, conduct a thorough medication review with SOTRs at all visits. Ask about new, changing, or symptomatic (pruritic, painful, bleeding) skin lesions, and perform a full-body skin exam. Palpate draining lymph nodes if the patient has a history of NMSC.¹⁵ AKs (FIGURE 3) should be treated aggressively with liquid nitrogen or field therapy. Lesions suspicious for NMSC should be biopsied and sent for histologic evaluation.²² Shave, punch, and excisional biopsies are all adequate techniques; however, because all cSCCs in SOTRs are considered high risk for aggressive features, biopsy should extend at least into the reticular dermis to allow evaluation for invasive disease.²²

Sun-protective measures (TABLE 1^{1,11,12,15,19-23}). Inquire about patients’ habits related to protection from the sun, their knowledge of recommended sun-protective measures, and risks associated with nonadherence. Recommended sun-protective measures include

• daily broad-spectrum sunscreen (SPF ≥ 30), reapplied every 2 hours of sun exposure, in accordance with labeling instructions²³
• sun-protective clothing (pants, long sleeves, hat, sunglasses)²³
• avoidance of tanning salons.¹⁵

SOTRs who adequately adhere to sun-protective measures might need vitamin D supplementation because sunscreen and sun-protective clothing inhibit cutaneous synthesis of vitamin D.¹⁵

Recommendations for treatment

Consider chemoprophylactic therapy for SOTRs who have had multiple prior cutaneous malignancies or multiple AKs.

Continue to: Topical chemoprophylaxis

Topical medications used for cSCC chemoprophylaxis include 5-fluorouracil (5-FU), photodynamic therapy (PDT), imiquimod, ingenol mebutate, topical retinoids, and diclofenac.²⁷ (See TABLE 2.^27-40) Of these, the latter 3 are used less commonly because of the small packaging size of ingenol mebutate and the relative lack of efficacy data for topical retinoids and diclofenac.²⁷ Imiquimod is often avoided when treating large surface areas because of the risk of systemic adverse effects associated with cytokine release.²⁷

5-FU is US Food and Drug Administration (FDA)-approved for the treatment of AKs, and is used off-label for treating cSCC in situ (Bowen disease). It is the most commonly used topical therapy for field disease.^27-29 5-FU is typically applied once or twice daily for 3 to 4 weeks. Common adverse effects include transient skin irritation and erythema.²⁷

PDT involves topical application of a photosensitizer, such as 5-aminolevulinic acid or methyl aminolevulinate, followed by exposure to a visible light source, leading to antitumor effects on gene expression and destruction of proliferating cells through production of reactive oxygen species.^30,31 Evidence is sufficient to support routine use of PDT for AKs and Bowen disease.³⁰ A mild sunburn-like reaction is common following PDT, with transient erythema and discomfort typically lasting 1 to 2 weeks but not typically necessitating analgesic therapy.²⁷

Imiquimod is a ligand that binds to and activates Toll-like receptor 7, leading to enhancement of the cell-mediated antitumor immune response and resultant tissue-­specific apoptosis coordinated by type 1 T-helper lymphocytes.³² Topical imiquimod cream is FDA approved for field treatment of AKs at 2.5%, 3.75%, and 5% concentrations; efficacy has been demonstrated in the SOTR population.^33,41 Multiple studies in immunocompetent patients have suggested that imiquimod might be slightly less efficacious than 5-FU.^42-44

The tolerability of field treatment with imiquimod has been called into question.²⁷ However, in a 2019 study comparing adverse reactions among 513 immunocompetent patients with field disease who were treated with either 5-FU 5% cream; imiquimod 5% cream; PDT with methyl aminolevulinate; or ingenol mebutate 0.015% gel, a similar or smaller percentage of patients treated with imiquimod reported moderate-to-severe itching, moderate-to-severe pain, and any adverse events, compared to patients treated with the other options.⁴⁴

Continue to: Diclofenac

Diclofenac is a nonsteroidal anti-­inflammatory drug that reversibly inhibits the enzymes cyclooxygenase-1 and ­cyclooxygenase-2, resulting in a decrease in the formation of inflammatory prostaglandins, which have been observed in chronically sun-damaged skin, AKs, and cSCC.^34,45 Diclofenac 3% gel, applied topically twice daily for 60 to 90 days has been approved by the FDA for treatment of AKs, in conjunction with sun avoidance.³⁴ Topical diclofenac has been demonstrated to be efficacious in treating AKs in the SOTR population^46,47; however, multiple meta-analyses using data from immunocompetent patients have demonstrated that topical diclofenac is inferior to other treatment options, particularly 5-FU, at achieving complete clearance of AKs.^43,48,49 Diclofenac might be a useful option when patient adherence is expected to be difficult because of adverse effects of therapy: Multiple studies have suggested that diclofenac might be more tolerable than other options.^43,48,50

Systemic chemoprophylaxis

Systemic therapies that have been used for chemoprophylaxis against cutaneous malignancy include nicotinamide, oral retinoids, capecitabine, and HPV vaccination. (See TABLE 2.^27-40)

Nicotinamide, the amide form of vitamin B₃, protects against cutaneous malignancy by aiding repair of DNA damaged by ionizing radiation, such as UV light.²⁷ Efficacy has been demonstrated in reducing development of new AKs and cSCC in immunocompetent patients with a history of more than 2 keratinocyte carcinomas within a 5-year span.^27,35 Nicotinamide is especially relevant to the SOTR population because it reduces the level of cutaneous immunity suppression induced by UV radiation without altering patients’ baseline immunity.^27,36

Because the intensity of immunosuppression and the individual immunosuppressants used affect the risk of nonmelanoma skin cancer, conduct a thorough medication review at all visits.

There are insufficient long-term follow-up data in the literature to assess the sustainability of the antitumor effects of nicotinamide; studies specific to the SOTR population have been underpowered for assessing its impact on formation of cSCC.^27,35Patients taking nicotinamide should be informed of the risk of liver failure at dosages > 3 g/d (antitumor efficacy has been demonstrated at 500 mg twice daily) and advised to avoid purchasing over-the-counter nicotinic acid or niacin as a substitute for nicotinamide, because of the increased incidence of flushing associated with their use.²⁷

Oral retinoids. Systemic retinoids—in particular, acitretin—are efficacious in reducing the risk of cSCC in SOTRs.^27,37,38 The primary drawback to cSCC prophylaxis with oral retinoids is a rebound effect, in which treatment discontinuation leads to a rapid return to baseline cSCC formation.²⁷

Continue to: Pregnancy must be avoided...

Pregnancy must be avoided while taking an oral retinoid. Because acitretin can persist in the body for years after discontinuation, its use should generally be avoided in patients of childbearing potential. An FDA black box warning states that patients of childbearing potential must be counseled to use 2 forms of birth control to avoid pregnancy for ≥ 3 years after cessation of oral acitretin. Prior to initiation of oral retinoid therapy, the following baseline laboratory tests should be obtained: complete blood count, creatinine, lipid panel, and liver function tests. For patients with a history of chronic kidney disease or renal transplantation, the lipid panel, liver function tests, and creatinine assay should be repeated with each dosage adjustment and every 3 months once goal-dosing is achieved.²⁷

Capecitabine is typically initiated with the help of Medical Oncology.^27,40 A prodrug metabolized by dihydropyrimidine dehydrogenase to 5-FU, capecitabine interacts with warfarin, leading to a significant increase in prothrombin time.³⁹ Other adverse effects associated with oral capecitabine include fatigue, palmar-plantar erythrodysesthesia, diarrhea, and, rarely, neutropenia. Although dihydropyrimidine dehydrogenase deficiency is rare, treatment with capecitabine in patients who have this enzyme deficiency might lead to severe toxicity or death.²⁷

HPV vaccination. HPV might play a role in the development of cutaneous malignancy, especially in immunosuppressed patients.^4,5 The utility of HPV vaccination in the prevention of NMSC has yet to be determined, but vaccination has been shown, in case reports, to be helpful in immunocompetent patients.^51,52 The immunogenicity of HPV vaccination in the SOTR population is uncertain, and the most common HPV types found in SOTRs are not specifically covered by available HPV vaccines.¹⁹

The role of immunosuppression reduction and immunosuppressive replacement

Both the degree of immunosuppression and the individual agents used can affect a patient’s risk of NMSC. Immunosuppression reduction should be considered if skin cancer poses a major risk to the patient’s health and if that risk outweighs the risk of graft rejection associated with immunosuppression reduction.²⁷ In a cohort of 180 kidney and liver SOTRs who developed de novo carcinoma (excluding NMSC) after transplantation, neither reduction of immunosuppression nor introduction of an mTOR inhibitor affected graft survival or oncologic treatment tolerance.⁵³ Because mTOR inhibitors have a protective effect against development of NMSC, they are the preferred choice of immunosuppressive agent from a dermatologic perspective.^1,27,54-57 Decisions regarding changes in immunosuppression are generally made by, or in collaboration with, the patient’s transplant physician.

Recommendations: Treating cSCC

Risk should guide strategy

Consider chemoprophylactic therapy for solid organ transplant recipients who have had multiple prior cutaneous malignancies or multiple AKs.

Small lesions of the trunk and extremities without high-risk features can be treated with a destructive method (eg, electrodessication and curettage). However, lesions of the head and neck and those found to have features consistent with an increased risk of recurrence or metastasis should be treated aggressively.^3,58,59

Continue to: Risk factors for invasive growth...

Risk factors for invasive growth, recurrence, or metastasis of cSCC in SOTRs are multiple lesions or satellite lesions, indistinct clinical borders, rapid growth, ulceration, and recurrence after treatment.⁶⁰ The risk of invasive growth, recurrence, and metastasis of cSCC also increases with size and location of the lesion, according to this framework⁶⁰:

• any size in scar tissue, areas of chronic inflammation, and fields of prior radiation therapy
• ≥ 0.6 cm on hands, feet, genitalia, and mask areas of the face (central face, eyelids, eyebrows, nose, lips, chin, mandible, and temporal, preauricular, postauricular, and periorbital areas)
• > 1 cm on cheeks, forehead, neck, and scalp
• > 2 cm on the trunk and extremities.

In addition, specific findings on histologic analysis portend increased risk of invasive growth, recurrence, or metastasis:

• poor differentiation
• deep extension of the tumor into subcutaneous fat
• perineural invasion or inflammation
• perivascular or intravascular invasion.

Treatment modalities

Mohs surgery is preferred to ensure margin clearance while preserving noninvolved tissue^3,7 (FIGURE 4). If Mohs surgery is not possible, the lesion should be excised with 3- to 10-mm margins.^3,60 Based on current literature, the roles of nodal staging, sentinel lymph node biopsy, and adjuvant therapy are not well defined, but it is likely that these interventions will play a pivotal role in the management of advanced cSCC in SOTRs in the future.³

Pregnancy must be avoided while taking an oral retinoid; because of its persistence, acitretin should generally be avoided in patients of childbearing potential.

Nonsurgical therapeutic options for primary or adjuvant treatment of cSCC include systemic chemotherapy, radiotherapy, and programmed cell death protein 1 inhibitors. (For more on treatment modalities, see TABLE 3.^3,7,58-61)

Recommendations: Treating BCC

BCC in SOTRs is treated similarly (TABLE 3^3,7,58-61) to how it is treated in the immunocompetent population—except that SOTRs require closer follow-up than nontransplant patients because they are at higher risk of recurrence and new NMSCs.³ Standard management after biopsy is either^3,61:

• Mohs surgery to ensure margin control (for most BCCs on the head and neck and those with clinical or histologic risk factors for recurrence or aggressive behavior)
• excision with a 4- or 5-mm margin or a destructive modality (for BCCs on the trunk and extremities without risk factors for recurrence).

Radiotherapy is an alternative for patients with high-risk BCCs who are unable to tolerate surgery.³

CORRESPONDENCE
Lindsey Collins, MD, Department of Dermatology, University of Oklahoma Health Sciences Center, 619 NE 13th Steet, Oklahoma City, OK 73104; [email protected]

The incidence of posttransplant malignancy among solid organ transplant recipients (SOTRs) is 10%; skin cancer, primarily nonmelanoma skin cancer (NMSC), constitutes 49.5% of all malignancies in this population.¹ The etiology of the increased risk of cutaneous malignancy in SOTR is multifactorial:

• The skin of SOTRs is photosensitive, compared to that of immunocompetent patients, thus predisposing SOTRs to carcinogenic damage resulting from exposure to UV light.²
• Immunosuppression plays a key role in increasing the risk of cutaneous malignancy by inhibiting the ability of the immune system to recognize and destroy tumor cells.³
• Human papillomavirus (HPV) can play a role in carcinogenesis by promoting molecular pathways to proliferation and survival of nascent tumor cells⁴;Times New Romanβ-HPV strains are disseminated ubiquitously in the skin of immunosuppressed patients.⁵
• Some medications administered after transplantation can be directly carcinogenic.

NMSC in SOTRs also differs qualitatively from NMSC in immunocompetent patients. Cutaneous squamous cell carcinoma (cSCC) (FIGUREs 1 and 2) is the most common skin cancer among SOTRs, whereas basal cell carcinoma (BCC) is the most common skin cancer in the general population.³ cSCC in the SOTR population tends to be more aggressive, with more rapid local invasion and an increased rate of both in-transit and distant metastases, leading to an increase in morbidity and mortality. Mortality of metastatic cSCC among SOTRs is approximately 50%, compared to 20% in an otherwise healthy population.^3,6-8

The problem is relevant to primary care

Screening. Because there is a demonstrated reduction in morbidity and mortality associated with early detection and treatment of NMSC, regular screening of skin is important in the SOTR population.⁹ A study in Ontario, Canada, from 1994 to 2012 and comprising 10,183 SOTRs, found that adherence to an annual skin check regimen for ≥ 75% of the observation period was associated with a 34% reduction in cutaneous BCC- and cSCC-­related morbidity or death (adjusted hazard ratio = 0.66; 95% CI, 0.48-0.92).¹⁰ Although routine follow-up with a dermatologist is recommended for SOTRs,^9,11-15 only 2.1% of patients in the Canadian study were fully adherent with annual skin examination, and 55% never visited a dermatologist.¹⁰ Consequently, primary care physicians can play a key role in skin cancer screening for SOTRs.

Education regarding the importance of protection from the sun is also an essential part of primary care. A 2018 study of SOTRs in Turkey demonstrated that¹⁶

• 46% expressed a lack of knowledge of the hazards of sun exposure
• 44% did not recall ever receiving medical advice regarding sun protection
• 89% did not wear sun-protective clothing
• 86% did not use sunscreen daily.

Multiple studies have demonstrated the positive effect that preventive education and attendance at a dermatology or skin cancer screening clinic can have on sun-protective behaviors among SOTRs.^9,16-18 In the Turkish study, 100% of patients who reported using sunscreen daily had been undergoing regular dermatologic examination.¹⁶

In this article, we review current management guidelines regarding the prevention and treatment of NMSC in SOTRs.

Recommendations for prevention

Screening skin exams (TABLE 1^{1,11,12,15,19-23}). Although definitive guidelines do not exist regarding the frequency of a screening skin exam for SOTRs, multiple frequency-­determining algorithms have been proposed.^11,12,15,19 The recommended frequency of a skin exam is based on history of skin cancer; for SOTRs, the most common recommendation¹⁹ is a full-body skin examination as follows:

• annually—when there is no history of skin cancer
• every 6 months—when there is a history of actinic keratoses (AKs; precancerous lesions that carry a risk of transforming into cSCC) or a single low-risk NMSC
• every 3 months—when there is a history of multiple NMSCs or a single high-risk NMSC
• every 1 to 3 months—when there is a history of metastatic disease.

Continue to: Other risk factors...

Other risk factors for NMSC to consider in SOTRs when determining an appropriate follow-up regimen include any of the following^{1,20,21,24-26}:

• male gender, fair skin, history of childhood sunburn, history of smoking
• lung or heart transplantation, history of episodes of transplant rejection, age ≥ 50 years at transplantation
• immunosuppression with calcineurin inhibitors, compared to mammalian target of rapamycin (mTOR) inhibitors
• immunosuppression with cyclosporine, compared to tacrolimus
• an immunosuppressive regimen with > 1 immunosuppressant or an increased degree of immunosuppression
• antithymocyte globulin within the first year posttransplantation.

Regular screening of skin is important in the solid organ transplant population.

Because the intensity of immunosuppression and individual immunosuppressants used affect the risk of NMSC, conduct a thorough medication review with SOTRs at all visits. Ask about new, changing, or symptomatic (pruritic, painful, bleeding) skin lesions, and perform a full-body skin exam. Palpate draining lymph nodes if the patient has a history of NMSC.¹⁵ AKs (FIGURE 3) should be treated aggressively with liquid nitrogen or field therapy. Lesions suspicious for NMSC should be biopsied and sent for histologic evaluation.²² Shave, punch, and excisional biopsies are all adequate techniques; however, because all cSCCs in SOTRs are considered high risk for aggressive features, biopsy should extend at least into the reticular dermis to allow evaluation for invasive disease.²²

Sun-protective measures (TABLE 1^{1,11,12,15,19-23}). Inquire about patients’ habits related to protection from the sun, their knowledge of recommended sun-protective measures, and risks associated with nonadherence. Recommended sun-protective measures include

• daily broad-spectrum sunscreen (SPF ≥ 30), reapplied every 2 hours of sun exposure, in accordance with labeling instructions²³
• sun-protective clothing (pants, long sleeves, hat, sunglasses)²³
• avoidance of tanning salons.¹⁵

SOTRs who adequately adhere to sun-protective measures might need vitamin D supplementation because sunscreen and sun-protective clothing inhibit cutaneous synthesis of vitamin D.¹⁵

Recommendations for treatment

Consider chemoprophylactic therapy for SOTRs who have had multiple prior cutaneous malignancies or multiple AKs.

Continue to: Topical chemoprophylaxis

Topical medications used for cSCC chemoprophylaxis include 5-fluorouracil (5-FU), photodynamic therapy (PDT), imiquimod, ingenol mebutate, topical retinoids, and diclofenac.²⁷ (See TABLE 2.^27-40) Of these, the latter 3 are used less commonly because of the small packaging size of ingenol mebutate and the relative lack of efficacy data for topical retinoids and diclofenac.²⁷ Imiquimod is often avoided when treating large surface areas because of the risk of systemic adverse effects associated with cytokine release.²⁷

5-FU is US Food and Drug Administration (FDA)-approved for the treatment of AKs, and is used off-label for treating cSCC in situ (Bowen disease). It is the most commonly used topical therapy for field disease.^27-29 5-FU is typically applied once or twice daily for 3 to 4 weeks. Common adverse effects include transient skin irritation and erythema.²⁷

PDT involves topical application of a photosensitizer, such as 5-aminolevulinic acid or methyl aminolevulinate, followed by exposure to a visible light source, leading to antitumor effects on gene expression and destruction of proliferating cells through production of reactive oxygen species.^30,31 Evidence is sufficient to support routine use of PDT for AKs and Bowen disease.³⁰ A mild sunburn-like reaction is common following PDT, with transient erythema and discomfort typically lasting 1 to 2 weeks but not typically necessitating analgesic therapy.²⁷

Imiquimod is a ligand that binds to and activates Toll-like receptor 7, leading to enhancement of the cell-mediated antitumor immune response and resultant tissue-­specific apoptosis coordinated by type 1 T-helper lymphocytes.³² Topical imiquimod cream is FDA approved for field treatment of AKs at 2.5%, 3.75%, and 5% concentrations; efficacy has been demonstrated in the SOTR population.^33,41 Multiple studies in immunocompetent patients have suggested that imiquimod might be slightly less efficacious than 5-FU.^42-44

The tolerability of field treatment with imiquimod has been called into question.²⁷ However, in a 2019 study comparing adverse reactions among 513 immunocompetent patients with field disease who were treated with either 5-FU 5% cream; imiquimod 5% cream; PDT with methyl aminolevulinate; or ingenol mebutate 0.015% gel, a similar or smaller percentage of patients treated with imiquimod reported moderate-to-severe itching, moderate-to-severe pain, and any adverse events, compared to patients treated with the other options.⁴⁴

Continue to: Diclofenac

Diclofenac is a nonsteroidal anti-­inflammatory drug that reversibly inhibits the enzymes cyclooxygenase-1 and ­cyclooxygenase-2, resulting in a decrease in the formation of inflammatory prostaglandins, which have been observed in chronically sun-damaged skin, AKs, and cSCC.^34,45 Diclofenac 3% gel, applied topically twice daily for 60 to 90 days has been approved by the FDA for treatment of AKs, in conjunction with sun avoidance.³⁴ Topical diclofenac has been demonstrated to be efficacious in treating AKs in the SOTR population^46,47; however, multiple meta-analyses using data from immunocompetent patients have demonstrated that topical diclofenac is inferior to other treatment options, particularly 5-FU, at achieving complete clearance of AKs.^43,48,49 Diclofenac might be a useful option when patient adherence is expected to be difficult because of adverse effects of therapy: Multiple studies have suggested that diclofenac might be more tolerable than other options.^43,48,50

Systemic chemoprophylaxis

Systemic therapies that have been used for chemoprophylaxis against cutaneous malignancy include nicotinamide, oral retinoids, capecitabine, and HPV vaccination. (See TABLE 2.^27-40)

Nicotinamide, the amide form of vitamin B₃, protects against cutaneous malignancy by aiding repair of DNA damaged by ionizing radiation, such as UV light.²⁷ Efficacy has been demonstrated in reducing development of new AKs and cSCC in immunocompetent patients with a history of more than 2 keratinocyte carcinomas within a 5-year span.^27,35 Nicotinamide is especially relevant to the SOTR population because it reduces the level of cutaneous immunity suppression induced by UV radiation without altering patients’ baseline immunity.^27,36

Because the intensity of immunosuppression and the individual immunosuppressants used affect the risk of nonmelanoma skin cancer, conduct a thorough medication review at all visits.

There are insufficient long-term follow-up data in the literature to assess the sustainability of the antitumor effects of nicotinamide; studies specific to the SOTR population have been underpowered for assessing its impact on formation of cSCC.^27,35Patients taking nicotinamide should be informed of the risk of liver failure at dosages > 3 g/d (antitumor efficacy has been demonstrated at 500 mg twice daily) and advised to avoid purchasing over-the-counter nicotinic acid or niacin as a substitute for nicotinamide, because of the increased incidence of flushing associated with their use.²⁷

Oral retinoids. Systemic retinoids—in particular, acitretin—are efficacious in reducing the risk of cSCC in SOTRs.^27,37,38 The primary drawback to cSCC prophylaxis with oral retinoids is a rebound effect, in which treatment discontinuation leads to a rapid return to baseline cSCC formation.²⁷

Continue to: Pregnancy must be avoided...

Pregnancy must be avoided while taking an oral retinoid. Because acitretin can persist in the body for years after discontinuation, its use should generally be avoided in patients of childbearing potential. An FDA black box warning states that patients of childbearing potential must be counseled to use 2 forms of birth control to avoid pregnancy for ≥ 3 years after cessation of oral acitretin. Prior to initiation of oral retinoid therapy, the following baseline laboratory tests should be obtained: complete blood count, creatinine, lipid panel, and liver function tests. For patients with a history of chronic kidney disease or renal transplantation, the lipid panel, liver function tests, and creatinine assay should be repeated with each dosage adjustment and every 3 months once goal-dosing is achieved.²⁷

Capecitabine is typically initiated with the help of Medical Oncology.^27,40 A prodrug metabolized by dihydropyrimidine dehydrogenase to 5-FU, capecitabine interacts with warfarin, leading to a significant increase in prothrombin time.³⁹ Other adverse effects associated with oral capecitabine include fatigue, palmar-plantar erythrodysesthesia, diarrhea, and, rarely, neutropenia. Although dihydropyrimidine dehydrogenase deficiency is rare, treatment with capecitabine in patients who have this enzyme deficiency might lead to severe toxicity or death.²⁷

HPV vaccination. HPV might play a role in the development of cutaneous malignancy, especially in immunosuppressed patients.^4,5 The utility of HPV vaccination in the prevention of NMSC has yet to be determined, but vaccination has been shown, in case reports, to be helpful in immunocompetent patients.^51,52 The immunogenicity of HPV vaccination in the SOTR population is uncertain, and the most common HPV types found in SOTRs are not specifically covered by available HPV vaccines.¹⁹

The role of immunosuppression reduction and immunosuppressive replacement

Both the degree of immunosuppression and the individual agents used can affect a patient’s risk of NMSC. Immunosuppression reduction should be considered if skin cancer poses a major risk to the patient’s health and if that risk outweighs the risk of graft rejection associated with immunosuppression reduction.²⁷ In a cohort of 180 kidney and liver SOTRs who developed de novo carcinoma (excluding NMSC) after transplantation, neither reduction of immunosuppression nor introduction of an mTOR inhibitor affected graft survival or oncologic treatment tolerance.⁵³ Because mTOR inhibitors have a protective effect against development of NMSC, they are the preferred choice of immunosuppressive agent from a dermatologic perspective.^1,27,54-57 Decisions regarding changes in immunosuppression are generally made by, or in collaboration with, the patient’s transplant physician.

Recommendations: Treating cSCC

Risk should guide strategy

Consider chemoprophylactic therapy for solid organ transplant recipients who have had multiple prior cutaneous malignancies or multiple AKs.

Small lesions of the trunk and extremities without high-risk features can be treated with a destructive method (eg, electrodessication and curettage). However, lesions of the head and neck and those found to have features consistent with an increased risk of recurrence or metastasis should be treated aggressively.^3,58,59

Continue to: Risk factors for invasive growth...

Risk factors for invasive growth, recurrence, or metastasis of cSCC in SOTRs are multiple lesions or satellite lesions, indistinct clinical borders, rapid growth, ulceration, and recurrence after treatment.⁶⁰ The risk of invasive growth, recurrence, and metastasis of cSCC also increases with size and location of the lesion, according to this framework⁶⁰:

• any size in scar tissue, areas of chronic inflammation, and fields of prior radiation therapy
• ≥ 0.6 cm on hands, feet, genitalia, and mask areas of the face (central face, eyelids, eyebrows, nose, lips, chin, mandible, and temporal, preauricular, postauricular, and periorbital areas)
• > 1 cm on cheeks, forehead, neck, and scalp
• > 2 cm on the trunk and extremities.

In addition, specific findings on histologic analysis portend increased risk of invasive growth, recurrence, or metastasis:

• poor differentiation
• deep extension of the tumor into subcutaneous fat
• perineural invasion or inflammation
• perivascular or intravascular invasion.

Treatment modalities

Mohs surgery is preferred to ensure margin clearance while preserving noninvolved tissue^3,7 (FIGURE 4). If Mohs surgery is not possible, the lesion should be excised with 3- to 10-mm margins.^3,60 Based on current literature, the roles of nodal staging, sentinel lymph node biopsy, and adjuvant therapy are not well defined, but it is likely that these interventions will play a pivotal role in the management of advanced cSCC in SOTRs in the future.³

Pregnancy must be avoided while taking an oral retinoid; because of its persistence, acitretin should generally be avoided in patients of childbearing potential.

Nonsurgical therapeutic options for primary or adjuvant treatment of cSCC include systemic chemotherapy, radiotherapy, and programmed cell death protein 1 inhibitors. (For more on treatment modalities, see TABLE 3.^3,7,58-61)

Recommendations: Treating BCC

BCC in SOTRs is treated similarly (TABLE 3^3,7,58-61) to how it is treated in the immunocompetent population—except that SOTRs require closer follow-up than nontransplant patients because they are at higher risk of recurrence and new NMSCs.³ Standard management after biopsy is either^3,61:

• Mohs surgery to ensure margin control (for most BCCs on the head and neck and those with clinical or histologic risk factors for recurrence or aggressive behavior)
• excision with a 4- or 5-mm margin or a destructive modality (for BCCs on the trunk and extremities without risk factors for recurrence).

Radiotherapy is an alternative for patients with high-risk BCCs who are unable to tolerate surgery.³

CORRESPONDENCE
Lindsey Collins, MD, Department of Dermatology, University of Oklahoma Health Sciences Center, 619 NE 13th Steet, Oklahoma City, OK 73104; [email protected]

The incidence of posttransplant malignancy among solid organ transplant recipients (SOTRs) is 10%; skin cancer, primarily nonmelanoma skin cancer (NMSC), constitutes 49.5% of all malignancies in this population.¹ The etiology of the increased risk of cutaneous malignancy in SOTR is multifactorial:

• The skin of SOTRs is photosensitive, compared to that of immunocompetent patients, thus predisposing SOTRs to carcinogenic damage resulting from exposure to UV light.²
• Immunosuppression plays a key role in increasing the risk of cutaneous malignancy by inhibiting the ability of the immune system to recognize and destroy tumor cells.³
• Human papillomavirus (HPV) can play a role in carcinogenesis by promoting molecular pathways to proliferation and survival of nascent tumor cells⁴;Times New Romanβ-HPV strains are disseminated ubiquitously in the skin of immunosuppressed patients.⁵
• Some medications administered after transplantation can be directly carcinogenic.

NMSC in SOTRs also differs qualitatively from NMSC in immunocompetent patients. Cutaneous squamous cell carcinoma (cSCC) (FIGUREs 1 and 2) is the most common skin cancer among SOTRs, whereas basal cell carcinoma (BCC) is the most common skin cancer in the general population.³ cSCC in the SOTR population tends to be more aggressive, with more rapid local invasion and an increased rate of both in-transit and distant metastases, leading to an increase in morbidity and mortality. Mortality of metastatic cSCC among SOTRs is approximately 50%, compared to 20% in an otherwise healthy population.^3,6-8

The problem is relevant to primary care

Screening. Because there is a demonstrated reduction in morbidity and mortality associated with early detection and treatment of NMSC, regular screening of skin is important in the SOTR population.⁹ A study in Ontario, Canada, from 1994 to 2012 and comprising 10,183 SOTRs, found that adherence to an annual skin check regimen for ≥ 75% of the observation period was associated with a 34% reduction in cutaneous BCC- and cSCC-­related morbidity or death (adjusted hazard ratio = 0.66; 95% CI, 0.48-0.92).¹⁰ Although routine follow-up with a dermatologist is recommended for SOTRs,^9,11-15 only 2.1% of patients in the Canadian study were fully adherent with annual skin examination, and 55% never visited a dermatologist.¹⁰ Consequently, primary care physicians can play a key role in skin cancer screening for SOTRs.

Education regarding the importance of protection from the sun is also an essential part of primary care. A 2018 study of SOTRs in Turkey demonstrated that¹⁶

• 46% expressed a lack of knowledge of the hazards of sun exposure
• 44% did not recall ever receiving medical advice regarding sun protection
• 89% did not wear sun-protective clothing
• 86% did not use sunscreen daily.

Multiple studies have demonstrated the positive effect that preventive education and attendance at a dermatology or skin cancer screening clinic can have on sun-protective behaviors among SOTRs.^9,16-18 In the Turkish study, 100% of patients who reported using sunscreen daily had been undergoing regular dermatologic examination.¹⁶

In this article, we review current management guidelines regarding the prevention and treatment of NMSC in SOTRs.

Recommendations for prevention

Screening skin exams (TABLE 1^{1,11,12,15,19-23}). Although definitive guidelines do not exist regarding the frequency of a screening skin exam for SOTRs, multiple frequency-­determining algorithms have been proposed.^11,12,15,19 The recommended frequency of a skin exam is based on history of skin cancer; for SOTRs, the most common recommendation¹⁹ is a full-body skin examination as follows:

• annually—when there is no history of skin cancer
• every 6 months—when there is a history of actinic keratoses (AKs; precancerous lesions that carry a risk of transforming into cSCC) or a single low-risk NMSC
• every 3 months—when there is a history of multiple NMSCs or a single high-risk NMSC
• every 1 to 3 months—when there is a history of metastatic disease.

Continue to: Other risk factors...

Other risk factors for NMSC to consider in SOTRs when determining an appropriate follow-up regimen include any of the following^{1,20,21,24-26}:

• male gender, fair skin, history of childhood sunburn, history of smoking
• lung or heart transplantation, history of episodes of transplant rejection, age ≥ 50 years at transplantation
• immunosuppression with calcineurin inhibitors, compared to mammalian target of rapamycin (mTOR) inhibitors
• immunosuppression with cyclosporine, compared to tacrolimus
• an immunosuppressive regimen with > 1 immunosuppressant or an increased degree of immunosuppression
• antithymocyte globulin within the first year posttransplantation.

Regular screening of skin is important in the solid organ transplant population.

Because the intensity of immunosuppression and individual immunosuppressants used affect the risk of NMSC, conduct a thorough medication review with SOTRs at all visits. Ask about new, changing, or symptomatic (pruritic, painful, bleeding) skin lesions, and perform a full-body skin exam. Palpate draining lymph nodes if the patient has a history of NMSC.¹⁵ AKs (FIGURE 3) should be treated aggressively with liquid nitrogen or field therapy. Lesions suspicious for NMSC should be biopsied and sent for histologic evaluation.²² Shave, punch, and excisional biopsies are all adequate techniques; however, because all cSCCs in SOTRs are considered high risk for aggressive features, biopsy should extend at least into the reticular dermis to allow evaluation for invasive disease.²²

Sun-protective measures (TABLE 1^{1,11,12,15,19-23}). Inquire about patients’ habits related to protection from the sun, their knowledge of recommended sun-protective measures, and risks associated with nonadherence. Recommended sun-protective measures include

• daily broad-spectrum sunscreen (SPF ≥ 30), reapplied every 2 hours of sun exposure, in accordance with labeling instructions²³
• sun-protective clothing (pants, long sleeves, hat, sunglasses)²³
• avoidance of tanning salons.¹⁵

SOTRs who adequately adhere to sun-protective measures might need vitamin D supplementation because sunscreen and sun-protective clothing inhibit cutaneous synthesis of vitamin D.¹⁵

Recommendations for treatment

Consider chemoprophylactic therapy for SOTRs who have had multiple prior cutaneous malignancies or multiple AKs.

Continue to: Topical chemoprophylaxis

Topical medications used for cSCC chemoprophylaxis include 5-fluorouracil (5-FU), photodynamic therapy (PDT), imiquimod, ingenol mebutate, topical retinoids, and diclofenac.²⁷ (See TABLE 2.^27-40) Of these, the latter 3 are used less commonly because of the small packaging size of ingenol mebutate and the relative lack of efficacy data for topical retinoids and diclofenac.²⁷ Imiquimod is often avoided when treating large surface areas because of the risk of systemic adverse effects associated with cytokine release.²⁷

5-FU is US Food and Drug Administration (FDA)-approved for the treatment of AKs, and is used off-label for treating cSCC in situ (Bowen disease). It is the most commonly used topical therapy for field disease.^27-29 5-FU is typically applied once or twice daily for 3 to 4 weeks. Common adverse effects include transient skin irritation and erythema.²⁷

PDT involves topical application of a photosensitizer, such as 5-aminolevulinic acid or methyl aminolevulinate, followed by exposure to a visible light source, leading to antitumor effects on gene expression and destruction of proliferating cells through production of reactive oxygen species.^30,31 Evidence is sufficient to support routine use of PDT for AKs and Bowen disease.³⁰ A mild sunburn-like reaction is common following PDT, with transient erythema and discomfort typically lasting 1 to 2 weeks but not typically necessitating analgesic therapy.²⁷

Imiquimod is a ligand that binds to and activates Toll-like receptor 7, leading to enhancement of the cell-mediated antitumor immune response and resultant tissue-­specific apoptosis coordinated by type 1 T-helper lymphocytes.³² Topical imiquimod cream is FDA approved for field treatment of AKs at 2.5%, 3.75%, and 5% concentrations; efficacy has been demonstrated in the SOTR population.^33,41 Multiple studies in immunocompetent patients have suggested that imiquimod might be slightly less efficacious than 5-FU.^42-44

The tolerability of field treatment with imiquimod has been called into question.²⁷ However, in a 2019 study comparing adverse reactions among 513 immunocompetent patients with field disease who were treated with either 5-FU 5% cream; imiquimod 5% cream; PDT with methyl aminolevulinate; or ingenol mebutate 0.015% gel, a similar or smaller percentage of patients treated with imiquimod reported moderate-to-severe itching, moderate-to-severe pain, and any adverse events, compared to patients treated with the other options.⁴⁴

Continue to: Diclofenac

Diclofenac is a nonsteroidal anti-­inflammatory drug that reversibly inhibits the enzymes cyclooxygenase-1 and ­cyclooxygenase-2, resulting in a decrease in the formation of inflammatory prostaglandins, which have been observed in chronically sun-damaged skin, AKs, and cSCC.^34,45 Diclofenac 3% gel, applied topically twice daily for 60 to 90 days has been approved by the FDA for treatment of AKs, in conjunction with sun avoidance.³⁴ Topical diclofenac has been demonstrated to be efficacious in treating AKs in the SOTR population^46,47; however, multiple meta-analyses using data from immunocompetent patients have demonstrated that topical diclofenac is inferior to other treatment options, particularly 5-FU, at achieving complete clearance of AKs.^43,48,49 Diclofenac might be a useful option when patient adherence is expected to be difficult because of adverse effects of therapy: Multiple studies have suggested that diclofenac might be more tolerable than other options.^43,48,50

Systemic chemoprophylaxis

Systemic therapies that have been used for chemoprophylaxis against cutaneous malignancy include nicotinamide, oral retinoids, capecitabine, and HPV vaccination. (See TABLE 2.^27-40)

Nicotinamide, the amide form of vitamin B₃, protects against cutaneous malignancy by aiding repair of DNA damaged by ionizing radiation, such as UV light.²⁷ Efficacy has been demonstrated in reducing development of new AKs and cSCC in immunocompetent patients with a history of more than 2 keratinocyte carcinomas within a 5-year span.^27,35 Nicotinamide is especially relevant to the SOTR population because it reduces the level of cutaneous immunity suppression induced by UV radiation without altering patients’ baseline immunity.^27,36

Because the intensity of immunosuppression and the individual immunosuppressants used affect the risk of nonmelanoma skin cancer, conduct a thorough medication review at all visits.

There are insufficient long-term follow-up data in the literature to assess the sustainability of the antitumor effects of nicotinamide; studies specific to the SOTR population have been underpowered for assessing its impact on formation of cSCC.^27,35Patients taking nicotinamide should be informed of the risk of liver failure at dosages > 3 g/d (antitumor efficacy has been demonstrated at 500 mg twice daily) and advised to avoid purchasing over-the-counter nicotinic acid or niacin as a substitute for nicotinamide, because of the increased incidence of flushing associated with their use.²⁷

Oral retinoids. Systemic retinoids—in particular, acitretin—are efficacious in reducing the risk of cSCC in SOTRs.^27,37,38 The primary drawback to cSCC prophylaxis with oral retinoids is a rebound effect, in which treatment discontinuation leads to a rapid return to baseline cSCC formation.²⁷

Continue to: Pregnancy must be avoided...

Pregnancy must be avoided while taking an oral retinoid. Because acitretin can persist in the body for years after discontinuation, its use should generally be avoided in patients of childbearing potential. An FDA black box warning states that patients of childbearing potential must be counseled to use 2 forms of birth control to avoid pregnancy for ≥ 3 years after cessation of oral acitretin. Prior to initiation of oral retinoid therapy, the following baseline laboratory tests should be obtained: complete blood count, creatinine, lipid panel, and liver function tests. For patients with a history of chronic kidney disease or renal transplantation, the lipid panel, liver function tests, and creatinine assay should be repeated with each dosage adjustment and every 3 months once goal-dosing is achieved.²⁷

Capecitabine is typically initiated with the help of Medical Oncology.^27,40 A prodrug metabolized by dihydropyrimidine dehydrogenase to 5-FU, capecitabine interacts with warfarin, leading to a significant increase in prothrombin time.³⁹ Other adverse effects associated with oral capecitabine include fatigue, palmar-plantar erythrodysesthesia, diarrhea, and, rarely, neutropenia. Although dihydropyrimidine dehydrogenase deficiency is rare, treatment with capecitabine in patients who have this enzyme deficiency might lead to severe toxicity or death.²⁷

HPV vaccination. HPV might play a role in the development of cutaneous malignancy, especially in immunosuppressed patients.^4,5 The utility of HPV vaccination in the prevention of NMSC has yet to be determined, but vaccination has been shown, in case reports, to be helpful in immunocompetent patients.^51,52 The immunogenicity of HPV vaccination in the SOTR population is uncertain, and the most common HPV types found in SOTRs are not specifically covered by available HPV vaccines.¹⁹

The role of immunosuppression reduction and immunosuppressive replacement

Both the degree of immunosuppression and the individual agents used can affect a patient’s risk of NMSC. Immunosuppression reduction should be considered if skin cancer poses a major risk to the patient’s health and if that risk outweighs the risk of graft rejection associated with immunosuppression reduction.²⁷ In a cohort of 180 kidney and liver SOTRs who developed de novo carcinoma (excluding NMSC) after transplantation, neither reduction of immunosuppression nor introduction of an mTOR inhibitor affected graft survival or oncologic treatment tolerance.⁵³ Because mTOR inhibitors have a protective effect against development of NMSC, they are the preferred choice of immunosuppressive agent from a dermatologic perspective.^1,27,54-57 Decisions regarding changes in immunosuppression are generally made by, or in collaboration with, the patient’s transplant physician.

Recommendations: Treating cSCC

Risk should guide strategy

Consider chemoprophylactic therapy for solid organ transplant recipients who have had multiple prior cutaneous malignancies or multiple AKs.

Small lesions of the trunk and extremities without high-risk features can be treated with a destructive method (eg, electrodessication and curettage). However, lesions of the head and neck and those found to have features consistent with an increased risk of recurrence or metastasis should be treated aggressively.^3,58,59

Continue to: Risk factors for invasive growth...

Risk factors for invasive growth, recurrence, or metastasis of cSCC in SOTRs are multiple lesions or satellite lesions, indistinct clinical borders, rapid growth, ulceration, and recurrence after treatment.⁶⁰ The risk of invasive growth, recurrence, and metastasis of cSCC also increases with size and location of the lesion, according to this framework⁶⁰:

• any size in scar tissue, areas of chronic inflammation, and fields of prior radiation therapy
• ≥ 0.6 cm on hands, feet, genitalia, and mask areas of the face (central face, eyelids, eyebrows, nose, lips, chin, mandible, and temporal, preauricular, postauricular, and periorbital areas)
• > 1 cm on cheeks, forehead, neck, and scalp
• > 2 cm on the trunk and extremities.

In addition, specific findings on histologic analysis portend increased risk of invasive growth, recurrence, or metastasis:

• poor differentiation
• deep extension of the tumor into subcutaneous fat
• perineural invasion or inflammation
• perivascular or intravascular invasion.

Treatment modalities

Mohs surgery is preferred to ensure margin clearance while preserving noninvolved tissue^3,7 (FIGURE 4). If Mohs surgery is not possible, the lesion should be excised with 3- to 10-mm margins.^3,60 Based on current literature, the roles of nodal staging, sentinel lymph node biopsy, and adjuvant therapy are not well defined, but it is likely that these interventions will play a pivotal role in the management of advanced cSCC in SOTRs in the future.³

Pregnancy must be avoided while taking an oral retinoid; because of its persistence, acitretin should generally be avoided in patients of childbearing potential.

Nonsurgical therapeutic options for primary or adjuvant treatment of cSCC include systemic chemotherapy, radiotherapy, and programmed cell death protein 1 inhibitors. (For more on treatment modalities, see TABLE 3.^3,7,58-61)

Recommendations: Treating BCC

BCC in SOTRs is treated similarly (TABLE 3^3,7,58-61) to how it is treated in the immunocompetent population—except that SOTRs require closer follow-up than nontransplant patients because they are at higher risk of recurrence and new NMSCs.³ Standard management after biopsy is either^3,61:

• Mohs surgery to ensure margin control (for most BCCs on the head and neck and those with clinical or histologic risk factors for recurrence or aggressive behavior)
• excision with a 4- or 5-mm margin or a destructive modality (for BCCs on the trunk and extremities without risk factors for recurrence).

Radiotherapy is an alternative for patients with high-risk BCCs who are unable to tolerate surgery.³

CORRESPONDENCE
Lindsey Collins, MD, Department of Dermatology, University of Oklahoma Health Sciences Center, 619 NE 13th Steet, Oklahoma City, OK 73104; [email protected]