Margin Recommendations for Cutaneous Malignancies in Immunocompetent and Immunocompromised Patients

Non-melanoma skin cancer (NMSC) is the most prevalent type of malignancy worldwide, with more than one million cases of NMSC diagnosed in the United States each year. The most common types of NMSC are basal cell carcinoma (BCC) and cutaneous squamous cell carcinoma (cSCC). Numerous risk factors exist for NMSC, including ultraviolet radiation, ionizing radiation, genetic disorders, chronic inflammation, and immunosuppression. Compared with the general population, patients who are chronically immunosuppressed have a significantly increased risk of developing NMSC; organ transplant recipients are 65 to 250 times more likely to develop cSCC and 10 to 16 times more likely to develop BCC. In immunosuppressed patients, prevention strategies, frequent surveillance, and early intervention are critical for reducing the morbidity and mortality associated with NMSC. When treating patients with NMSC, it is important to determine if they are at low risk or high risk for recurrence, as this has important prognostic implications and affects their recommended treatment algorithm. Several characteristics including lesion size, location, borders, histopathologic features, and patient history of prior radiation therapy or immunocompromised state factor into the determination of whether a patient is at low risk or high risk. Based on the 2021 National Comprehensive Cancer Network (NCCN) guidelines, all patients who are immunosuppressed should be classified as having high-risk lesions. In 2015, the European Journal of Cancer published a consensus-based interdisciplinary guideline that summarized the appropriate diagnostic and treatment algorithms for cSCC. The authors recommend a 5 mm margin for low-risk cSCC.1 This aligns with the NCCN's recommended 4 to 6 mm margins for cSCC without high-risk features (Fig. 1). Although these margins are adequate for low-risk cSCC, it is widely accepted that patients with high-risk lesions have worse outcomes, and thus require a more aggressive treatment approach to ensure negative margins are obtained. Numerous population-based studies have demonstrated that organ transplant recipients with cSCC are more likely to have aggressive disease. Manyam et al. conducted a multi-institutional study that examined outcomes of immunosuppressed and immunocompetent patients treated for cSCC of the head and neck.2 This study demonstrated that compared with immunocompetent patients, immunosuppressed patients have a significantly lower locoregional recurrence-free survival (86.1% vs 47.3%, P < .0001) and progression-free survival (71.6% vs 38.7%, P = .002). CCPDMA can be done via a variety of methods, including Mohs micrographic surgery (MMS), intraoperative frozen section analysis, and permanent section analysis with delayed wound closure. Leibovitch et al. published a prospective, multicenter study that reported a 5-year recurrence rate of 3.9% for cSCC treated with MMS, which is lower than the previously cited 5.7% to 18.7% recurrence rates for standard surgical excision (SSE).3 CCPDMA is the preferred treatment, because it allows for evaluation of 100% of the excised margins; however, the decision regarding which method of CCPDMA to employ often depends upon an institution's capabilities and the tumor location and characteristics. For instance, MMS is not available in all practice settings and it typically takes longer than SSE. Additionally, MMS often cannot be used for tumors that are very large or are in locations that require meticulous surgical dissection to preserve critical anatomic structures. As shown in Figure 1, in situations where CPPDMA is not feasible, patients may undergo SSE. If SSE is pursued, the NCCN recommends margins greater than 4 to 6 mm; however, they do not give specific margin recommendations due to the wide variety of characteristics that define a high-risk tumor. The European consensus-based guideline suggests 10 mm margins for high-risk cSCC that is not amenable to CCPDMA.1 The prognosis for patients with low-risk BCC is quite favorable, as these tumors are generally slow growing and rarely metastasize. For these low-risk tumors, the NCCN supports the use of curettage and electrodesiccation or SSE with 4 mm margins (Fig. 1). Conversely, high-risk BCC has been found to have variable recurrence rates and a more aggressive pathology. Although BCC is not associated with the same level of morbidity and mortality as cSCC in immunosuppressed patients, a retrospective study by Mehrany et al. demonstrated that patients with chronic lymphocytic leukemia were 14 times more likely to have BCC recurrence than immunocompetent patients.4 The NCCN guidelines recommend classifying all BCCs in immunosuppressed patients as potentially high-risk tumors. A randomized clinical trial published in 2014 by van Loo et al. found that treating high-risk facial BCC with MMS resulted in fewer recurrences when compared with SSE.5 For primary high-risk BCC, the authors report a 10-year cumulative probability of recurrence of 4.4% after MMS and 12.2% after SSE, although this was not statistically significant (P = .100). For recurrent BCC, the 10-year recurrence probabilities after MMS and surgical excision were 3.9% and 13.5%, respectively (P = .023). Based on these findings, the authors advocate for the use of MMS over SSE for the treatment of high-risk primary and recurrent facial BCC. As demonstrated in Figure 1, the NCCN guidelines recommend utilizing CCPDMA, specifically with MMS or intraoperative frozen section assessment, for high-risk BCC. If CCPDMA is not possible, then the NCCN recommends SSE with margins wider than that recommended for low-risk BCC (4 mm); however, they do not give specific margin recommendations. Instead, they suggest margin modification based on tumor- or patient-specific factors. Several factors such as tumor size, location, and histopathological features, must be considered when deciding on surgical margins for NMSC. For low-risk cSCC, 4 to 6 mm margins are recommended, whereas for low-risk BCC, the recommendation is for 4 mm margins. Per the NCCN guidelines, chronic immunosuppression places patients with cSCC and BCC into the high-risk category. For patients with high-risk cSCC and BCC, the standard of care is CCPDMA; however, if this is not possible, then SSE with 4 to 6 mm and 4 mm margins, respectively, is recommended. These recommendations are based upon one randomized clinical trial5 (level 1), one prospective case series3 (level 2), two retrospective reviews2,4 (level 3), and one statement of expert opinion1 (level 5).