Skin cancers are the most common types of cancer and their incidence has shown an increasing of ∼4 to 8% per year over the last 40 years (1). The majority of skin cancers (∼97%) are non-melanoma skin cancers, mainly represented by basal cell (80%) and squamous cell carcinomas (20%) (2).

Despite the low mortality rates and the rare occurrence of metastases, non-melanoma skin cancers may be locally invasive and exhibit relapse following treatment, with significant morbidity (3,4).

Recurrence is better defined as a persistent disease and is mainly correlated with inadequate local treatment (5–7). The use of intra-operative frozen section remains controversial in the surgical treatment of non-melanoma skin cancer, being commonly considered an optional tool, the reliability and effectiveness of which remain questionable (8–14).

A large retrospective study was therefore conducted to examine 670 surgical excisions of non-melanoma skin cancers of the head and neck in 481 patients over a period of nine years, between May, 2002 and December, 2011, at the Plastic and Reconstructive Surgery Unit of the University of Pavia, Salvatore Maugeri Research and Care Institute, Pavia, Italy. Additionally, indications, limits and effectiveness of the intra-operative frozen section biopsy are discussed in detail.

In the whole sample, of 670 non-melanoma skin cancers 597 demonstrated a complete surgical excision in healthy tissue (89.10%). Within these completely excised tumors, recurrence was observed only in one case of basal cell carcinoma (0.17%), one year post-operatively. Intra-operative frozen section biopsy was required in 71 of 670 cases. The distribution of the intra-operative frozen section biopsies per anatomical site is shown in Table I.

Following the histological examination, of the 71 frozen section biopsies 65 (91.55%) were confirmed as intra-operative and 6 (8.45%) were not (Table II). The success rate (complete surgical excision) in the intra-operative frozen section biopsy cohort was 84.51%, with a completely excised tumor in 60 of 71 cases. The success rate in the resected cases without an intra-operative frozen section biopsy was 89.65%, with a complete excision in 537 of 599 cases. The success rate per anatomical site, with and without the use of an intra-operative frozen section biopsy, is evident in Tables III and IV.

Findings of the present study have demonstrated the paradoxical ineffectiveness of an intra-operative frozen section biopsy in pursuing higher rates of radical excision in nonmelanoma skin cancers. Such an outcome requires a more accurate interpretation with regard to the intrinsic limits of such a procedure. An intra-operative frozen section is potentially unreliable for two main reasons: intrinsic technical limits and subjective indication. Technically, a frozen specimen does not exhibit as many histological fine details as a formalin-embedded one. Therefore, the diagnostic accuracy of a frozen section report is always somewhat rough and imprecise. A frozen section is always required for one or more specimen margins, according to the surgeon’s subjective clinical judgement to avoid potential failure of the surgeon and consequently the whole procedure.

Identifying a definite clinical margin of a non-melanoma skin carcinoma may be difficult in various circumstances. The sclerosing basal cell carcinoma usually features ill-defined borders resembling small patches of scleroderma with peripheral growth and central sclerosis. A multi-focal skin cancer within the context of a field cancerisation also shows ill-defined margins. Recurrence of a skin carcinoma following a failed previous surgical or conservative treatment therefore also poses the same issue.

In our experience, an intra-operative frozen section biopsy was required when the surgeon doubted the appropriateness of a previously outlined resection margin in an apparently healthy tissue. Such a subjectively based practice a priori vitiated the sample distribution and randomization with distortion of the inclusion criteria and subsequent reduction of the cases with an intra-operative frozen section biopsy, compared to those without. This finding therefore explains the evident and statistically non-significant results of the comparison between the two groups, as well as the poor performance with the use of a supposedly advantageous tool.

Despite such a relevant methodological defect that is correlated with the limits of a retrospective study to a certain extent, a noteworthy similarity in the success rate (82.35 vs. 82.28%, odds ratio >1) between resected cases of intra-operative frozen section biopsy and those without was identified in tumors of the orbito-palpebral anatomical subgroup (96 records) (Table III). Thus, the analysis was refined within this subgroup by restricting the sample to an overall of 59 cases where the tumor involved the lid margin and the medial and lateral canthi. Tumors exhibit an aggressive attitude with potential early invasion of the orbit and skull base. A radical excision at these sites usually requires a technically demanding functional reconstruction (15). The refined statistical analysis is likely to eventually suggest the effectiveness of an intra-operative frozen section in obtaining a higher success rate (87.50 vs. 69.77%, odds ratio 2.98) in the surgical treatment of non-melanoma skin cancers of the eyelids (Table IV).

This retrospective study provides a large and homogeneous sample of non-melanoma skin cancer in a western post-industrial society Caucasian population living in a temperate geographical area.

Treatment options available include curettage, desiccation, cryotherapy, topical regimens of 5-fluorouracil (5-FU) or imiquimod (INN), photo-dynamic therapy and radiotherapy. However, surgery remains the mainstay in the treatment of non-melanoma skin cancer (16,17). Radical excision of the neoplasm with a wide margin in healthy tissue is the key for success in this field (18). Accuracy in pre- and/or intra-operative outlining of the appropriate excision margin in healthy tissue remains an open issue. Several options and a discussion of their benefits and drawbacks have addressed the issue. Mohs micrographic surgery provides conservative excision of tissue with microscopic intra-operative examination of the excised tissue with proper orientation and colour coding of the specimens. The advisability of Mohs micrographic surgery in the treatment of non-melanoma skin cancer has long been debated in the literature, with equally motivated irreconcilable opinions from advocates and detractors (19). The main advantage of such an approach is the one-stage tumor excision in clear margins, while the disadvantages are its being time-consuming and patient discomfort. A previous study (20) using a large patient cohort investigated the long-term outcome of Mohs micrographic surgery for basal cell carcinomas of the face. Results of that study demonstrated a 5-year recurrence rate of 4.5% for the lesions, 3.2% for primary tumors and 6.7% for recurrent ones. The rapid paraffin sections are a potential alternative to Mohs micrographic surgery as results obtained can be reported in 24 h. Nevertheless, such a procedure is multi-staged, time-consuming and does not prevent patient discomfort. The frozen section is an optional tool utilized to intra-operatively assess one or more margins of a surgically excised specimen. Its advisability, reliability and effectiveness are as debated as Mohs micrographic surgery with a corresponding equal distribution of supporters and detractors (8–14).

In our experience, an intra-operative frozen section was required to check a complete excision of the neoplasm in one or more specimen marginal spots. In particular, an intra-operative frozen section was mostly required in the critical anatomical sites of the head, such as the nose, cheeks, eyelids, chin, lips and forehead. Thus, a potentially persistent disease from an incomplete primitive excision would demand a far more aggressive and disabling secondary surgery.

Our findings suggest the routine use of an intra-operative frozen section biopsy in the surgical treatment of non-melanoma skin tumors involving the eyelids and canthi.

Nevertheless, the effectiveness of an intra-operative frozen section biopsy is always correlated with the surgeon’s subjective clinical assessment, even in the modern era of sophisticated and accurate objective diagnostic tools. The forthcoming use of the promising confocal laser scanning microscopy is likely to provide a non-invasive view to pre-operatively identify adequate resection margins (21,22).