The incidence of nonmelanoma skin cancer (NMSC) has risen, leading to higher treatment costs.1 The reported incidence of basal cell carcinoma (BCC) in Spain is 253 per 100000 person-years, while the incidence of squamous cell carcinoma (SCC) is 38.2 per 100000 person-years.2 The relative risk (RR) of a subsequent skin cancer for patients diagnosed with an NMSC versus persons in the general population ranges from 29.1 for a new BCC and 13.5 for a new SCC within 3 years of the initial NMSC diagnosis.3 Previous studies of the appearance of subsequent cancers in patients diagnosed with NMSC suggest that they appear in 22.6% of patients followed for a mean of 28.3 months4 and in 67.8% of those followed for 10 years.5 These figures oblige us to follow patients to detect new tumors in order to lower mortality.

Patients who underwent Mohs micrographic surgery (MMS) may be a subgroup at higher risk of subsequent tumors.6

The aim of this study was to assess the risk of developing a new tumor in a cohort of patients diagnosed with NMSC who were initially treated with MMS and to identify factors associated with higher risk.

The REGESMOHS registry has been described previously.7,8 Briefly, REGESMOHS stores data for a prospective cohort of patients registered starting in July 2013 at 22 Spanish hospitals that perform at least 1 MMS per week. Both private and public health system hospitals participated. All adult patients were registered consecutively as they were evaluated for MMS. Only minors and patients found legally incompetent were excluded.

Variables were grouped as they included recorded during clinical visits. Information registered on the first visit were demographic data; history of diseases or conditions associated with immunosuppression, such as hematologic diseases, transplant recipients, prolonged immunosuppression, and diabetes mellitus; clinical and histopathologic features of the tumor; and prior treatments. In the second visit we recorded surgical variables: type of Mohs surgery, anesthesia, hospital admission, anticoagulant and antiplatelet management during the procedure, size of the surgical defects and reconstructions, complementary treatments, duration of surgery, complications, and intraoperative morbidity. In the third visit short-term results and complications were recorded. In successive visits up to at least 1 year, we assessed the outcome of surgery and registered recurrences and the development of new tumors. Patients who had more than 1 tumor treated with Mohs surgery during the registry period and follow-up will be described in this study, although only the initial tumor was registered in REGESMOHS.

Information was collected according to a set protocol in an online system (OpenClinica, version 3.1, Waltham, MA, USA). Data quality was monitored online on a continuing basis and in situ at each participating hospital annually to ensure compliance with the data collection protocol in each center and verify that data were consistent with source documents.

A total of 4768 patients underwent MMS; 4397 (92%) were diagnosed with BCC and 371 (8%) with SCC (Table 1). Follow-up continued for a mean (SD) of 2.4 (1.6) years for patients with BCCs and 2.2 (1.5) years for those with SCCs.

A new malignant tumor was diagnosed in 1201 patients (25%). In 1013 of them (21%) the diagnosis was BCC, in 154 (3%) it was SCC, and in 20 (0.4%) it was melanoma. In 960 patients (22%) whose initial tumor was a BCC, the new tumor was also a BCC; in 212 cases (3%) it was an SCC. In patients whose MMS procedure removed an SCC, the subsequent tumor was a BCC in 53 cases (14%) and an SCC in 33 (9%).

A single new tumor was diagnosed in 756 patients (16%), while 2 new tumors appeared in 270 (6%), and 3 or more appeared in 175 (4%).

Most of the new tumors were removed with conventional surgery (856 patients [76%]). However, MMS was used in 168 cases (15%) and topical treatments (imiquimod, photodynamic therapy, electrosurgery, or cryotherapy) in 97 (9%). Radiotherapy was used in 3 patients and other treatments in 2 patients (vismodegib in 1 of them). One patient declined treatment.

The incidence of new tumors of any type was 107 (95% CI, 101–113) per 1000 person-years. The incidences for BCC, SCC, and melanoma, respectively, were 90 (95% CI, 85–96) per 1000 person-years, 14 (95% CI, 12–16) per 1000 person-years, and 2 (95% CI, 1–3) per 1000 person-years (Table 1).

The appearance of a new tumor was associated with male sex and age (Table 2). The median (IQR) age was 73.9 years (65.9–80.9 years) in the group with subsequent tumors and 69.9 years (58.1–79.5 years) in the group with none.

Demographic, clinical, and histologic data for both groups are summarized in Table 2.

Table 3 shows the risk factors for the appearance of new tumors that were identified by univariable analysis. Table 4 shows the risk factors identified by multivariable analysis. After adjusting the models, we found that the main risk factors were multiple tumors on diagnosis (RR, 4.59; 95% CI, 2.95–7.13), immunosuppression (RR, 2.11; 95% CI, 1.44–3.08), and male sex (RR, 1.61; 95% CI, 1.39–1.85) (Table 4).

Our study shows a high incidence of subsequent skin cancer after MMS treatment of NMSCs, especially in men, patients initially presenting with multiple tumors, and patients who are immunocompromised.

Previous studies also reported that patients with NMSC are at greater risk of developing subsequent tumors.3,9–15 Domínguez-Cruz et al.4 found a 22.6% risk in a retrospective cohort of 926 patients diagnosed with NMSC; mean follow-up was 6.4 years (range, 0.5–12.1 years). Revenga et al.3 estimated a RR of 29.1 for a new BCC and 13.6 for a new SCC in a retrospective cohort of 118 patients initially diagnosed with NMSC. In a prospective cohort of 1805 patients with this diagnosis, Karagas et al.11 calculated the risk of subsequent NMSC to be 17%, 35%, and 50% at 1, 3, and 5 years, respectively.

A study by Schinstine & Goldman6 of patients with characteristics similar to ours—with MMS-treated NMSCs and followed for 2 years—reported a frequency of multiple new tumors of 19.8% (in 87 of 440 patients) and a frequency of single new tumors of 19.5% (in 86 of 440). Our study population of 4768 patients followed for a mean of 2.4 (1.6) years, was representative of patients with NMSCs treated with MMS in Spain. We registered a lower percentage (2%) of cases of multiple tumors at diagnosis, yet the frequency of subsequent tumors was somewhat higher in our patients, at 25% (in 1201), than in the study of by Schinstine & Goldman. The frequencies of subsequent tumors after MMS treatment reported from studies with fewer than 5 years of follow-up have ranged from 14.6%13 to 22%.14 We calculated an incidence of 107 (101–113) per 1000 person-years for new NMSCs of any type. The incidences per 1000 person-years were 90 (85–96) for BCC, 14 (12–16) for SCC, and 2 (1–3) for melanoma (Table 1). Fig. 1 is a graph of the cumulative incidence of new skin cancers.

Figure 1.

Curve showing the cumulative incidence of new tumors. The curve depicts the survival time from Mohs micrographic surgery until the appearance of a new tumor in a context of competing risks, where death is considered the main competing factor.

(0.1MB).

The strongest risk factor for developing a subsequent NMSC in our cohort was the presence of multiple tumors on diagnosis (RR, 4.59), consistent with the literature.5,6,12 Immunosuppression (RR, 2.11) was another important factor. Some studies have excluded immunocompromised patients when calculating risk for subsequent NMSC.4 Male sex (RR, 1.61,) was also important, consistent with the findings of Karagas et al.,11 although other studies have seen similar frequencies in both sexes.6,13 Prior nonsurgical treatment (RR, 1.78) also conferred risk for a new tumor in our study, as did whether the initial MMS-treated tumor was recurrent (RR, 1.18) or not.

Strengths of our study include its prospective design, the large population size, the representativeness of the MMS-treated patients with NMSC in Spain, and the long-term follow-up of cases. A possible limitation is the difficulty of organizing follow-up for some of our patients, especially those living in areas far from referral hospitals. Supporting the relevance of this limitation is the fact that such residence or the need for hospitalization were protective factors, possibly indicating bias since recurrence would have been more difficult to detect in such patients. If bias was present, the real incidence of new tumors would be even higher than the incidence we report and would therefore support our conclusions.

We conclude that subsequent skin tumors are very frequent in patients whose initial tumors are treated with MMS, particularly in men, immunocompromised patients, or those who have multiple tumors on diagnosis. Our findings suggest that there is a need for long-term follow-up of patients after MMS. In addition, full-body skin examination is probably necessary, rather than the examination only of the operated zone.

REGESMOHS(the registry of Mohs micrographic surgery procedures performed in 22 Spanish hospitals) was promoted by the Healthy Skin Foundation of the Spanish Academy of Dermatology and Venereology (AEDV) with funding from Roche Pharma. This study also received funding from Sun Pharma. Neither Roche Pharma nor Sun Pharma participated in the design of the study or data analysis and interpretation.

The authors declare no conflicts of interest.