Interventions After First Post-Transplant Cutaneous Squamous Cell Carcinoma: A Proposed Decision Framework.

Cutaneous squamous cell carcinoma (CSCC) is a major cause of morbidity and mortality after organ transplant. Many patients subsequently develop multiple CSCC following a first CSCC, and the risk of metastasis and death is significantly increased compared to the general population. Post-transplant CSCC represents a disease at the interface of dermatology and transplant medicine. Both systemic chemoprevention and modulation of immunosuppression are frequently employed in patients with multiple CSCC, yet there is little consensus on their use after first CSCC to reduce risk of subsequent tumors. While relatively few controlled trials have been undertaken, extrapolation of observational data suggests the most effective interventions may be at the time of first CSCC. We review the need for intervention after a first post-transplant CSCC and evidence for use of various approaches as secondary prevention, before discussing barriers preventing engagement with this approach and finally highlight areas for future research. Close collaboration between specialties to ensure prompt deployment of these interventions after a first CSCC may improve patient outcomes.

Merkel cell carcinoma in a young man with AIDS-related Kaposi sarcoma.

Merkel cell carcinoma (MCC) is a rare, aggressive primary neuroendocrine carcinoma of the skin that can present in immunocompromised patients. Kaposi sarcoma (KS) is an indolent angioproliferative tumor associated with human herpesvirus 8 (HHV8). The concurrence of both MCC and KS is rare, and there have been limited cases reported in the literature. We present a rare case of concurrent MCC and KS in an immunocompromised patient. To our knowledge, this is the first report of MCC and KS described in the same histopathological specimen. A 37-year-old Black male with a history of recurrent AIDS-related KS involving bilateral lower extremities was evaluated for a tender nodule on the left posterior leg. A punch biopsy was consistent with MCC. Magnetic resonance imaging brain and full-body positron emission tomography/computed tomography (PET/CT) scan were without evidence of distant metastasis. The patient underwent wide local excision with negative margins and completed postoperative radiation therapy. However, he later developed cutaneous metastasis of MCC to the left medial thigh and excision revealed residual MCC with adjacent KS. Treatment is still ongoing with pembrolizumab for both KS and MCC.

Field cancerization: Treatment.

The goal of field cancerization treatment is to reduce the risk of developing keratinocyte carcinoma. Selecting the appropriate therapy depends on the degree of field cancerization and the number of invasive cutaneous squamous cell carcinomas. Other considerations include treatment efficacy, cost, side effects, and patient preference. Field therapies are preferred because they address clinically visible disease and subclinical atypia. However, lesion-directed therapies are useful for lesions that are more difficult to treat or those where a histologic diagnosis is required. Patients with extensive field cancerization benefit from a combination of field-directed and lesion-directed treatments. The second article in this continuing medical education series provides a framework to guide evidence-based decision making for field cancerization treatment.

Field cancerization: Definition, epidemiology, risk factors, and outcomes.

Field cancerization was first described in 1953 when pathologic atypia was identified in clinically normal tissue surrounding oropharyngeal carcinomas. The discovery of mutated fields surrounding primary tumors raised the question of whether the development of subsequent tumors within the field represented recurrences or additional primary tumors. Since this initial study, field cancerization has been applied to numerous other epithelial tissues, including the skin. Cutaneous field cancerization occurs in areas exposed to chronic ultraviolet radiation, which leads to clonal proliferations of p53-mutated fields and is characterized by multifocal actinic keratoses, squamous cell carcinomas in situ, and cutaneous squamous cell carcinomas. In the first article in this continuing medical education series, we define field cancerization, review the available grading systems, and discuss the epidemiology, risk factors, and outcomes associated with this disease.

Predicting skin cancer in organ transplant recipients: development of the SUNTRAC screening tool using data from a multicenter cohort study.

Skin cancer is a common post-transplant complication. In this study, the Skin and Ultraviolet Neoplasia Transplant Risk Assessment Calculator (SUNTRAC) was developed to stratify patients into risk groups for post-transplant skin cancer. Data for this study were obtained from the Transplant Skin Cancer Network (TSCN), which conducted a multicenter study across 26 transplant centers in the United States. In total, 6340 patients, transplanted from 2003 and 2008, were included. Weighted point values were assigned for each risk factor based on beta coefficients from multivariable modeling: white race (9 points), pretransplant history of skin cancer (6 points), age ≥ 50 years (4 points), male sex (2 points), and thoracic transplant (1 point). Good prognostic discrimination (optimism-corrected c statistic of 0.74) occurred with a 4-tier system: 0-6 points indicating low risk, 7-13 points indicating medium risk, 14-17 points indicating high risk, and 18-22 points indicating very high risk. The 5-year cumulative incidence of development of skin cancer was 1.01%, 6.15%, 15.14%, and 44.75%, for Low, Medium, High, and Very High SUNTRAC categories, respectively. Based on the skin cancer risk in different groups, the authors propose skin cancer screening guidelines based on this risk model.

Initial skin cancer screening for solid organ transplant recipients in the United States: Delphi method development of expert consensus guidelines.

Skin cancer is the most common malignancy affecting solid organ transplant recipients (SOTR), and SOTR experience increased skin cancer-associated morbidity and mortality. There are no formal multidisciplinary guidelines for skin cancer screening after transplant, and current practices are widely variable. We conducted three rounds of Delphi method surveys with a panel of 84 U.S. dermatologists and transplant physicians to establish skin cancer screening recommendations for SOTR. The transplant team should risk stratify SOTR for screening, and dermatologists should perform skin cancer screening by full-body skin examination. SOTR with a history of skin cancer should continue regular follow-up with dermatology for skin cancer surveillance. High-risk transplant patients include thoracic organ recipients, SOTR age 50 and above, and male SOTR. High-risk Caucasian patients should be screened within 2 years after transplant, all Caucasian, Asian, Hispanic, and high-risk African American patients should be screened within 5 years after transplant. No consensus was reached regarding screening for low-risk African American SOTR. We propose a standardized approach to skin cancer screening in SOTR based on multidisciplinary expert consensus. These guidelines prioritize and emphasize the need for screening for SOTR at greatest risk for skin cancer.

Association of antinuclear antibody status with clinical features and malignancy risk in adult-onset dermatomyositis.

BACKGROUND: The clinical significance of antinuclear antibody (ANA) status in adults with dermatomyositis (DM) has yet to be fully defined. OBJECTIVE: We compared the incidence of amyopathic disease, risk of malignancy, and clinical findings in ANA+ and ANA- patients with adult-onset DM. METHODS: This was a retrospective cohort study of patients with ANA+ or ANA- adult-onset DM determined by enzyme-linked immunosorbent assay. RESULTS: Of 231 patients, 140 (61%) were ANA+ and 91 (39%) were ANA-. Compared with the ANA- patients, the ANA+ patients had a lower frequency of dysphagia (15% vs 26% [P = .033]) and heliotrope rash (38% vs 53% [P = .026]). In all, 54 patients (23%) developed malignancy within 3 years of diagnosis of their DM; 11% of the ANA+ patients developed malignancy versus 43% of the ANA- patients (P < .001). There was a strong association between ANA positivity and lower likelihood of malignancy in multivariable analysis (odds ratio, 0.16; P < .001). Conversely, ANA positivity was not associated with amyopathic disease (odds ratio, 0.94; P = .87). LIMITATIONS: The retrospective nature of the study was a limitation. CONCLUSION: In patients with adult-onset DM, ANA negativity is associated with increased likelihood of development of malignancy within 3 years of diagnosis of their DM. Particularly close follow-up and frequent malignancy screening may be warranted in ANA- individuals with DM.

Pediatric melanomas often mimic benign skin lesions: A retrospective study.

BACKGROUND: Childhood melanoma can be misdiagnosed because of its rarity and atypical presentation. OBJECTIVE: We sought to correlate the clinical appearance of pediatric melanomas with Breslow depth and clinical behavior, and to identify diagnostic errors made by dermatologists and nondermatologist physicians. METHODS: This was a retrospective review of Mayo Clinic records of children and young adults 21 years of age or younger with a diagnosis of primary cutaneous melanoma between January 2000 and January 2015. RESULTS: Pediatric melanomas that mimicked benign skin lesions were more often deeper (>1 mm; odds ratio 5.48; P = .002) and had a higher T stage (odds ratio [T2, T3, or T4] 6.28; P = .001) than melanomas with a clinically malignant appearance. Of pediatric melanomas, 66% originally diagnosed as benign melanocytic lesions exhibited changes in size, shape, and color. LIMITATIONS: Sample size and retrospective design are limitations. CONCLUSIONS: Benign-appearing pediatric skin lesions with a history of evolution, bleeding, or ulceration should raise suspicion for melanoma. Melanomas demonstrating these features are associated with a higher Breslow depth and T stage. Although biopsy of all lesions that exhibit change in children is not practical, safe, or desired, close monitoring is recommended.

Sequential Curettage, 5-Fluorouracil, and Photodynamic Therapy for Field Cancerization of the Scalp and Face in Solid Organ Transplant Recipients.

BACKGROUND: Field cancerization with actinic keratoses and squamous cell carcinoma in situ (AK/SCCIS) represents a common therapeutic challenge in solid organ transplant recipients (SOTRs). These patients often show inadequate responses to methods traditionally used as monotherapy (e.g., topical chemotherapy). OBJECTIVE: To describe the clinical outcomes and feasibility of a sequential approach to treatment of field cancerization in SOTRs. METHODS: Four SOTRs with field cancerization of the scalp and/or face were treated using a sequential approach. Light curettage of hypertrophic lesions was followed by application of 5-fluorouracil 5% cream twice daily for 5 days and photodynamic therapy (PDT) with 1-hour incubation on day 6. Pain level during and after PDT was recorded. Photographs were obtained immediately before and after treatment and at follow-up appointments. RESULTS: All 4 patients tolerated this approach well and demonstrated excellent responses to treatment with complete or near-complete clinical resolution of AK/SCCIS lesions. Patients remained free of AK/SCCIS based on clinical examination 1 to 6 months after treatment. CONCLUSION: For SOTRs with field cancerization, sequential therapy represents a viable therapeutic regimen with good tolerability and durable clinical response. This approach warrants further investigation to determine which therapeutic combinations have optimal tolerability and efficacy.

A systematic review of outcome data for dermatofibrosarcoma protuberans with and without fibrosarcomatous change.

BACKGROUND: To our knowledge, no systematic review of dermatofibrosarcoma protuberans (DFSP) outcomes based on the presence or absence of fibrosarcomatous (FS) change has been performed. OBJECTIVE: We sought to compare available outcome data for DFSP versus DFSP-FS. METHODS: The literature was searched for DFSP and DFSP-FS reports with outcome data (local recurrence, metastasis, or death from disease). Chi-square tests were calculated to determine whether DFSP and DFSP-FS significantly differed in risk of local recurrence, metastasis, and death from disease. RESULTS: In all, 24 reports containing 1422 patients with DFSP and 225 with DFSP-FS are summarized. Risk of local recurrence, metastasis, and death from disease in DFSP-FS was significantly higher as compared with DFSP (local recurrence 29.8% vs 13.7%, risk ratio 2.2 [95% confidence interval 1.7-2.9]; metastasis 14.4% vs 1.1%, risk ratio 5.5 [95% confidence interval 4.3-7.0]; and death from disease 14.7% vs 0.8%, risk ratio 6.2 [95% confidence interval 5.0-7.8]). There was no significant difference in DFSP-FS outcomes based on proportion of FS change within tumors. LIMITATIONS: This study is based on previously reported data from different hospitals with no uniform process for reporting FS change. The impact of confounders (age, immune status, tumor location, treatment) could not be evaluated because of limited data. CONCLUSION: Based on available retrospective data, risk of metastasis and death is elevated in DFSP-FS as compared with DFSP. Even a low degree of FS involvement portends worse outcomes.

Standardizing Retrospective Observational Research in Cutaneous Squamous Cell Carcinoma: Expert Panel Guidelines from ITSCC.

Importance: Cutaneous squamous cell carcinoma (CSCC) is the second most common malignant disease in the US. Although it typically carries a good prognosis, a subset of CSCCs are highly aggressive, carrying regional and distant metastatic potential. Due to its high incidence, this aggressive subset is responsible for considerable mortality, with an overall annual mortality estimated to equal or even surpass melanoma. Despite this morbidity, CSCC is excluded from national cancer registries, making it difficult to study its epidemiology and outcomes. Therefore, the bulk of the CSCC literature is composed of single-center and multi-institutional retrospective cohort analyses. Given variations in reporting measures and analyses in these studies, interpretability between studies and the ability to pool results are limited. Objective: To define standardized reporting measures for retrospective CSCC studies. Findings: An expert panel was convened to determine standardized guidelines for recording and analyzing retrospective CSCC data. A total of 13 dermatologists and dermatologic surgeons with more than 5 years of posttraining experience and considerable experience with performing CSCC outcomes research were recruited to the panel. Consensus recommendations were achieved for CSCC retrospective study reporting measures, definitions, and analyses. Conclusions and Relevance: The recommendations in this report present the potential to standardize future CSCC retrospective studies. With such standardization, future work may have greater interstudy interpretability and allow for pooled analyses.

Advances in Topical Treatments of Cutaneous Malignancies.

Surgical excision has been the preferred treatment for cutaneous malignancies, but can be affected by various considerations. Noninvasive, self-administered topical treatments represent an alternative option. The aim of this review was to evaluate and summarize evidence-based recommendations for topical treatments of basal cell carcinoma (BCC), cutaneous squamous cell carcinoma (CSCC), in situ melanoma (MIS), and extramammary Paget's disease (EMPD). Studies were reviewed on PubMed. Included studies were summarized, assessed for biases, and assigned a level of evidence to develop treatment recommendations. For the treatment of superficial BCC, complete clearance rates ranged from 90 to 93% for 5% 5-fluorouracil (5-FU) and 71 to 76% for imiquimod (IMQ). For the treatment of nodular BCC, clearance rates for photodynamic therapy (PDT) were 91% at 3 months, with a sustained lesion clearance response rate of 76% after 5 years of follow-up. Clearance rates were 53 to 76% with IMQ. For squamous cell carcinoma in situ, clearance rates ranged from 52 to 98% for PDT, 67 to 92% for 5-FU, and 75 to 93% for IMQ. For MIS, clearance rates ranged from 53 to 92% for IMQ. For EMPD, 54% of 110 patients in cohort studies and case series had a clinical complete response with IMQ. While surgical intervention remains the standard of care for skin cancer, non-invasive, self-administered topical treatments are highly desirable alternative options. Ultimately, the patient and provider should find a treatment modality that aligns with the patient's expectations and maintenance of quality of life.

Catastrophic Merkel Cell Carcinoma in a Liver Transplant Recipient.

Merkel cell carcinoma (MCC) is a rare skin cancer, is difficult to diagnose, and carries a high mortality rate. Solid organ transplant recipients (SOTR) are at a disproportionately increased risk of MCC and other malignancies due to chronic immunosuppression. We discuss the case of a 47-year-old woman with a remote history of liver transplant on chronic immunosuppression with tacrolimus for over a decade who presented for a third recurrence of MCC on her left forearm. This case report underscores the importance of a risk-stratified approach to regular dermatologic care and skin cancer screening in this vulnerable population.

The utility of teledermatology in the evaluation of skin lesions.

INTRODUCTION: Past studies have shown mixed results about the accuracy of store-and-forward (SAF) teledermatology in the evaluation of skin lesions. The objective of this study is to determine the accuracy of SAF teledermatology in the diagnosis of skin lesions and biopsy decision compared to in-person clinical evaluation. METHODS: Histories and photographs of skin lesions gathered at clinic visits were sent as SAF consults to teledermatologists, whose diagnoses and biopsy decisions were recorded and compared statistically to the clinic data.Results and Discussion: We enrolled 206 patients with 308 lesions in the study. The study population was composed of 50% males (n = 104), and most patients were white (n = 179, 87%) and not Hispanic/Latino (n = 167, 81%). There was good concordance for biopsy decision between the clinic dermatologist (CD) and teledermatologist (TD) (Cohen's kappa (κ) = 0.51), which did not significantly differ when melanocytic lesions were excluded (κ = 0.54). The sensitivity and specificity of teledermatology based on biopsy decision was 0.71 and 0.85, respectively. Overall concordance in first diagnosis between the CD and TD was good (κ = 0.60). While there was no difference between CD and TD in proportion of correct diagnoses compared to histopathology, two skin cancers presentations were missed by TD. Study limitations included sample size, enrolment bias and differing amounts of teledermatologist case experience. Teledermatology has good concordance in diagnosis and biopsy decision when compared to clinic dermatology. Teledermatology may be utilized in the evaluation of skin lesions to expand access to dermatologic care.

Cutaneous squamous cell carcinoma staging may influence management in users: A survey study.

PURPOSE: This study aims to determine whether there is consensus regarding staging and management of cutaneous squamous cell carcinoma (CSCC) across the various specialties that manage this disease. MATERIALS AND METHODS: A survey regarding CSCC high-risk features, staging, and management was created and emailed to cutaneous oncology experts including dermatology, head and neck surgery/surgical oncology, radiation oncology, and medical oncology. RESULTS: One hundred fifty-six (46%) of 357 invited physicians completed the survey. Depth of invasion (92%), perineural invasion (99%), histologic differentiation (85%), and patient immunosuppression (90%) achieved consensus (>80%) as high-risk features of CSCC. Dermatologists were more likely to also choose clinical tumor diameter (79% vs. 54%) and histology (99% vs. 66%) as a high-risk feature. Dermatologists were also more likely to utilize the Brigham and Women's Hospital (BWH) staging system alone or in conjunction with American Joint Committee on Cancer (AJCC) (71%), whereas other cancer specialists (OCS) tend to use only AJCC (71%). Respondents considered AJCC T3 and higher (90%) and BWH T2b and higher (100%) to be high risk and when they consider radiologic imaging, sentinel lymph node biopsy, post-operative radiation therapy, and increased follow-up. Notably, a large number of respondents do not use staging systems or tumor stage to determine treatment options beyond surgery in high-risk CSCC. CONCLUSION: This survey study highlights areas of consensus and differences regarding the definition of high-risk features of CSCC, staging approaches, and management patterns between dermatologists and OCS. High-risk CSCC is defined as, but not limited to, BWH T2b and higher and AJCC T3 and higher, and these thresholds can be used to identify cases for which treatment beyond surgery may be considered. Dermatologists are more likely to utilize BWH staging, likely because BWH validation studies showing advantages over AJCC were published in dermatology journals and discussed at dermatology meetings. Additional data are necessary to develop a comprehensive risk-based management approach for CSCC.