Surgical treatment with free margins (R0 resection) is the treatment of choice for most localized skin malignancies.1 Micrographic surgery with margin control or Mohs surgery (MMS) has shown the highest cure rate and lowest rate of recurrences in the management of multiple skin tumors.2–5 MMS has numerous indications, and has gone through multiple variations since its original description.6 In addition to its advantages in terms of lower local recurrence rates, recent studies have suggested lower rates of locoregional recurrence, with reduced rates of in-transit metastases or satellitosis in head and neck melanoma, as well as a lower rate of distant metastases, and even increased survival.7–9 Despite its numerous advantages, MMS has several drawbacks. Among these are high cost, the need for a surgical and technical team available with advanced training, adequate equipment, and the time needed when several stages are required.10,11 In response to these difficulties, especially when it comes to relying on a specialized technical team at the precise moment of surgery for in vivo analysis, at the end of the 1970s, variations to the original MMS technique started being developed to allow for deferred analyses, using paraffin-fixed sections. These techniques have been reported in the scientific medical literature as deferred Mohs, slow Mohs, 3D histology, complete circumferential peripheral and deep margin assessment with permanent sections, Muffin technique, perimeter technique, quadrant technique, Tübingen technique, rush paraffin sections, staged marginal and central excision technique, or paraffin sections with tissue mapping before delayed surgical defect closure. Although these techniques are different, they analyze 100% of the margins of the tumor, its sides and deep inside the tumor (conventional histopathological examination analyzes <1% of the margins), and are performed through 90° incisions. In all of these procedures, the excised tissue is marked for precise topographic orientation.12,13 These techniques can be performed with both frozen and paraffin sections. However, in the routine clinical practice, they are mostly performed using paraffin-fixed sections. To avoid confusing nomenclature, we will refer to all variations of MMS with paraffin sections as paraffin-embedded margin-controlled Mohs micrographic surgery (PMMS). With this technique, complete analysis of the surgically excised piece can be achieved, as with the MMS without having to perform an analysis immediately after the surgical procedure. This deferred analysis has shown its effectiveness not only in basal cell carcinoma (BCC) and cutaneous squamous cell carcinoma (cSCC), but also in others in which immediate (fresh) analysis is more complex and can require immunohistochemical analysis, such as lentigo maligna melanoma (LMM), atypical fibroxanthoma (AFX), dermatofibrosarcoma protuberans (DFSP) or extramammary Paget's disease, among others.14–16 A comparison between MMS surgery and PMMS is shown in Table 1. In this article we will review different types of PMMS, as well as their indications and outcomes in terms of local recurrence in the surgical treatment of diverse skin malignancies.

A narrative search of the literature was conducted in Medline and Google Scholar during May 2023 using the keyterms ‘Mohs surgery’, ‘Mohs surgery in paraffin’, ‘slow Mohs’, ‘3D histology’, ‘complete circumferential peripherals and deep margin assessment with permanent sections’, ‘Muffin-technique surgery’, ‘perimeter technique surgery’, ‘quadrant technique surgery’, ‘Tubingen technique’, ‘rush paraffin sections’, ‘staged marginal and central excision technique’, ‘spaghetti technique’ whether isolated or in combination with the keywords ‘basal cell carcinoma’, ‘squamous cell carcinoma’, ‘melanoma’, ‘lentigo maligna melanoma’, ‘acral lentiginous melanoma’, ‘dermatofibrosarcoma protuberans’, ‘atypical fibroxanthoma’, ‘microcystic adnexal carcinoma’, ‘Merkel cell carcinoma’, ‘extramammary Paget's disease’, and ‘cutaneous adnexal tumors’. Prospective and retrospective studies, case series of ≥10 patients, clinical trials, and systematic reviews (SR) and meta-analyses (MA) were included. Regarding rare tumors, some series with <10 patients and satisfactory methodological quality were collected. Two of the authors (MMP and DMC) performed the search and selected the articles.

MMS is an effective treatment variant for numerous cutaneous malignancies. It has achieved significant superiority vs WLE to treat recurrent and high-risk non-melanoma skin cancer.93 However, multiple difficulties need to be overcome to perform MMS, and PMMS can be easier to implement, and has significant advantages.16 Histopathological examinations may differ when comparing frozen vs paraffin sections. In a classic study of 258 samples analyzed in both ways, it was found that the initial biopsy diagnosis differed from the Mohs frozen and paraffin section diagnoses in 20% of the cases.94 We should mention that, although both conventional MMS and PMMS theoretically analyze 100% of the margins, in actuality, on numerous occasions they give “false negatives” in frozen sections, caused by the lower tissue quality of these sections. On the contrary, paraffin sections tend to offer better tissue quality, allowing small tumor remains to be analyzed, and reducing the rates of false negatives.16,20,95 Regarding its effectiveness, PMMS has shown a lower rate of recurrence vs MMS in the management of BCC in RCTs.31,33,34 In the case of cSCC, no studies have ever compared MMS to PMMS. However, a recent study stated that in 27.8% of the re-examined cSCC treated with MMS reporting free margins, sections tumor outgrowths were still visible in immunohistochemistry that had not been detected via HE staining. Therefore, PMMS could play a fundamental role through deferred immunohistochemistry, and in the detection of atypical patterns.16,94 PMMS has shown rates of recurrence ranging from 3% to 10% at 5 years.19,23,27,28,39-41,43 Frozen sections of MMS are generally insufficient to analyze melanocytic tumors,87 and PMMS has shown lower rates of relapse in LM and LMM vs WLE.68 Regarding survival, although some studies did not show an increased overall survival rate with MMS and PMMS vs WLE in the management of LM and LMM,96 recent studies have revealed a greater overall survival in patients treated with PMMS vs WLE, especially on the head and scalp.7,97 Regarding infrequent tumors such as DFSP, lower rates of recurrence have been reported with PMMS vs MMS.72 However, data in primary cases found no difference in overall survival for patients treated with WLE vs PMMS.98 As for MCC, it has not been possible to demonstrate that PMMS presents a lower rate of recurrence or better survival than MMS,14,23,40,85,86 but may allow narrower margins, and fewer functional and esthetic complications. Given the difficulty of in vivo examination and the possibility of failure in the analysis of rare tumors, PMMS has been proposed as the technique of choice for excision of AFX, PDS, extramammary Paget's disease and sebaceous carcinoma, among others. However, most of the data found in the literature allude to small series.

Regarding the disadvantages of PMMS, the need for several surgical sessions and the possibility of architectural changes of the piece due to repeated suture threads stand out.99 However, immediate closure is possible. This can be performed using skin grafting or biomembranes, secondary intention healing or primary closure, among other techniques that do not produce significant anatomical distortions.16 In these cases, we recommend taking pictures of the surgical defect before and after reconstruction to achieve an exact topographic correlation if a positive margin is found. In any case, complex reconstructions are ill-advised until all margins are reported to be tumor-free. Although PMMS can require surgical interventions to be performed on different days, which could increase costs, the decrease in recurrences vs other techniques and, therefore, the need for large secondary surgeries, along with functional and cosmetic complications, could, in the long run, be more cost effective: studies on the cost effectiveness of PMMS are required. When performing PMMS, a good and fluent communication between the dermatologist and the pathologist is essential, to avoid long waiting times that may increase the patient's anxiety while waiting for the histopathological results. In our hospital, we have extensive experience performing both MMS and PMMS, and sometimes we even combine these techniques during resection of a complex or large tumor, or in specific anatomical areas.

We should mention that in a recent study no major postoperative complications were found with PMMS vs MMS.100

The present literature review is limited by the fact that it is a narrative review and not a SR of the scientific medical literature currently available, or a MA. Similarly, many of the studies included have small or medium sized samples, a retrospective design, heterogeneous methodologies, or use different surgical techniques. Additionally, the terminology of MMS vs PMMS is, sometimes, controversial in the literature, with both terms overlapping in numerous articles. These factors make it difficult to extrapolate or generalize our findings.

Complete resection with free surgical margins is the gold standard in the management of skin cancer. PMMS requires minimal training for the dermatologic surgeon, the pathology technician, and the pathologist. PMMS does not require special equipment either, and can be very useful and effective to treat diverse skin neoplasms, both frequent tumors such as BCC, SCC, or LMM, and rare neoplasms such as DFSP or AFX, among others. PMMS techniques also allow better analysis of tumor remains than MMS and could reduce the rate of false negative. We want to emphasize that it can be adopted even in small hospitals or clinics and significantly reduce the risk of incomplete tumor resection, and/or local recurrence.

The authors declare that they have no conflict of interest.