Abstract
In a prospective study, a large number of patients with basal cell carcinomas (BCCs) and squamous cell carcinomas (SCCs) underwent surgery using three dimensional (3D) histology and were evaluated with respect to local recurrence. The excised tumours were treated using 3D-histology with a routine paraffin procedure until the surgical margins were clear of tumour. Prospective evaluation of recurrence-free survival and overall survival of 5227 primary BCCs in 3320 patients and 615 invasive primary SCCs in 600 patients was conducted in the form of a letter-based follow-up with feedback from the patients and the referring physicians. The mean follow-up period was 5 years. In the BCC collective, 36 out of 3320 patients developed local recurrence (1%, calculated as a percentage of treated BCCs: 0.7%). In the SCC collective, 20 local recurrences appeared (3%). The recurrence rate for SCCs with desmoplasia was 24%, whilst the recurrence rate for common types of SCC without desmoplasia was 1%. Surgery followed by 3D histology results in very low recurrence rates for BCC and SCC with no additional effort compared with the normal histopathological procedure.
Basal cell carcinomas (BCCs) and squamous cell carcinomas (SCCs) are the major histological types of non-melanoma skin cancer and are the most frequently reported malignancies in white populations . The average age of patients with BCCs is over 60 years , and that of patients with SCCs is over 70 years . Most tumours are located in the head and neck area. Studies on large collectives of patients with malignant epithelial skin tumours are rare. This may be due to the patients’ advanced age and to the relatively low malignancy of the tumours.
BCCs are defined as slow-growing, locally invasive malignant skin tumours which tend to infiltrate the surrounding tissue in an asymmetric, three-dimensional (3D) fashion, in part with very fine strands that may not be obvious even on intraoperative inspection. One of the main problems is the risk of local recurrence of the tumour after treatment . The metastatic potential of SCC is about 4% and is not the topic of this study .
Incomplete resection of non-melanoma skin cancers is associated with a relatively high rate of recurrent tumours . SCCs and BCCs can cause extensive destruction of tissue, particularly on the face, if left untreated or if treated inadequately . Tumour removal (prevention of recurrent tumours), protection of healthy skin and aesthetic outcome are important aspects of skin tumour treatment .
The aim of this study was to describe a large number of patients with BCCs and SCCs following 3D histology-guided surgery regarding local recurrences and to compare recurrence rates to the overall survival (OS).
Methods
The authors followed-up 3320 patients with 5227 primary BCCs (an additional 478 patients had no follow-up) and 600 patients with 615 invasive primary SCCs (an additional 53 patients had no follow-up). The patients underwent surgery between January 1990 and December 2000 after being hospitalized because of tumour size and location. All tumours were excised by 3D histology-guided surgery.
Patients with the Gorlin-Goltz syndrome ( n = 4), patients with BCC–SCC collision tumours ( n = 6) and patients with recurrent tumours who had been previously treated elsewhere ( n = 517) were excluded from the study.
For prospective analysis, the following information was collected from patients with recurrent tumours: date of birth and sex; date of surgical excision of the primary tumour; location of the primary tumour; differentiation of the tumour; maximum diameter (in mm) and the largest diameter perpendicular to the maximum diameter; excision margin (in mm) according to the probability of subclinical outgrowth ; histological evaluation of the complete 3D excision margins (3D histology) in a routine paraffin technique available 20 h after surgery; and number of re-operations until all margins were tumour-free. If applicable, the date of recurrence and the patient’s date of death were also recorded.
Normally, a skin tumour is excised with a certain excision margin. This depends on the visible tumour diameter, histological type of the tumour and the anatomical localisation . Normally, the excised tissue is divided into parallel sections for histopathological investigation (bread-loaf technique), but this method has diagnostic gaps. 3D histology examines the entire 3D border of the tumour specimen by first cutting the entire vertical excisional margin as a small vertical strip and then cutting a horizontal strip of the whole base of the excision site. These strips of fresh tissue are flattened and placed into cassettes for routine paraffin histology . After rush fixation for 2 h in 60 °C hot formalin, all specimens are embedded in paraffin and sectioned according to routine procedures. Twenty hours later, haematoxylin–eosin stained slides are read by a dermatopathologist or surgeon experienced in the histopathological interpretation of malignant skin tumours . Dissecting the specimens in this way and carrying out the histopathological examination demands no more effort than conventional procedures ( Fig. 1 ). Using paraffin sections provides a more sensitive technique to detect tumour outgrowths than using frozen sections. ‘Mohs’ micrographic surgery (MMS) is similar to this approach, using an oblique incision and frozen sections . In their clinical practice, the authors use excision margins in the range 1–10 mm according to the criteria: tumour type; tumour diameter; and location. In these cases the tumour is excised with a relatively large excision margin relative to the tumour diameter. The defect is closed immediately if it is possible using simple primary closure or a graft. In the case of a complex reconstructive procedure the authors let the defect open. 99% of all operations were performed with tumescent local anaesthesia. Patients were reoperated on, until tumour-free margins were obtained. If the defect is closed directly, a reoperation can be planned after wound healing or promptly.
Data from all the patients were prospectively collected at the Comprehensive Cancer Centre (CCC), Tübingen, Germany after obtaining informed patient consent. In a follow-up, patients received letters from CCC (1 and 4 years after the operation for BCC and yearly for SCC) asking them to visit their primary dermatologist’s office. Patients who did not answer received up to two reminders.
Part of the letter was a questionnaire that asked the patients’ physicians to report local recurrence of the cancer, regional lymph node metastases or the death of the patient.
The questionnaires were sent back to CCC by the doctors or patients or, in case of death, by the patients’ relatives. The complete after-care collective included 3320 patients with 5227 primary BCCs and 600 patients with 615 primary SCCs. 531 patients did not answer any letters and had to be excluded from the analysis.
Suspicious lesions reported by the physicians or other hospital departments were documented by the CCC. If a local recurrence was suspected, the patients were asked to visit the hospital.
Patient data were collected in a computer database. The patients’ baseline demographic and clinical characteristics were summarized using descriptive statistics.
Local recurrence-free survival (RFS) and OS were calculated. RFS was defined as the time from the date of primary surgery of the tumour to the date of diagnosis of a local recurrence. OS was measured from the date of primary surgery to the date of death. Death from progressive SCC was documented.
Probabilities were estimated by the Kaplan–Meier method and graphically described by Kaplan–Meier curves. All statistical analyses were performed with the use of SAS software, version 9.1. This is a prospective, mono-central, non-randomised study.
Results
The mean excision margin was 3.4 mm (range 1–10 mm). In difficult locations, the margins were small to preserve skin. 55% of all patients had immediate wound closure. A second procedure was necessary in 45% of cases due to residual tumour found in 3D histology. The excision margins of the re-excisions ranged from 1 to 10 mm, depending on the tumour mass seen in the margins and the location of the tumour. The mean excision margin in re-operations was 2.9 mm. The frequency of multiple re-operations (more than 2) was 9%.
Basal cell carcinomas
The mean patient age was 66 years; 59% of the 3320 patients were male. The clinically visible diameters of the 5227 tumours are shown in Fig. 2 .
The CCC reported 181 potential local recurrences which were all biopsied (145 were histologically negative, 36 were recurrent BCC). During follow-up, seven of these patients with recurrence were treated in other locations, the other 29 patients were treated in the authors’ hospital. In terms of the total collective of 3320 patients, 36 local recurrences yield a recurrence rate of 1%, whilst in terms of the total number of tumours the recurrence rate was 0.7%. Over the entire study period, the median time to recurrence was 25 months (5–68 months).
The recurrent tumours were mostly located on the face, with a majority on the nose, lips or cheek. The visible diameters of the recurrent tumours are shown in Fig. 2 . Recurrent tumours seemed to have a smaller diameter than the primary tumour. Most recurrent tumours were sclerosing ( n = 13), followed by solid ( n = 9) and superficial types ( n = 7).
During the study period, between 1990 and 2005, 742 patients died. The probability of local RFS was 99% (95% confidence interval: 98–99%) at 3 years and 98% (95% confidence interval: 96–98%) at 5 years ( Fig. 3 ).
Squamous cell carcinomas
The mean patient age was 76 years; 63% of the 600 patients were male. Most of the SCCs ( n = 564) in the total collective were of the non-desmoplastic type. The visible sizes of the 600 tumours are shown in Fig. 2 .
The CCC reported 130 potential local recurrences which were all biopsied (110 were histologically negative, 20 were recurrent SCC). In terms of the total collective of 600 patients, 20 local recurrences yield a recurrence rate of 3%. Over the study period, the minimum time to local recurrence was 2 months; the maximum was 57 months; the median was 12 months.
In the study collective, 51 primary tumours showed desmoplasia. During follow-up, 12 of the recurrent tumours also showed desmoplasia. The remaining eight recurrent tumours from desmoplastic primary SCCs were non-desmoplastic (common). The recurrence rate was 24% for the desmoplastic type and 1% for the common type.
Local recurrences occurred mainly on the lips and the cheek. There were no differences with respect to the location of the primary tumour. The recurrent tumour diameters are shown in Fig. 2 .
By the end of the study period, 275 patients had died (46% of all patients). Of the 600 patients with primary SCCs, 26 (5%) had metastases. Six patients died as a result of the metastases (1%). The probability of local RFS was 93% (95% confidence interval: 90–94%) at 3 years and 91% (95% confidence interval: 87–93%) at 5 years ( Fig. 3 ).
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