Elsevier

The Lancet Oncology

Volume 9, Issue 8, August 2008, Pages 713-720
The Lancet Oncology

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Analysis of risk factors determining prognosis of cutaneous squamous-cell carcinoma: a prospective study

https://doi.org/10.1016/S1470-2045(08)70178-5Get rights and content

Summary

Background

Cutaneous squamous-cell carcinomas (SCC) are among the most common cancers capable of metastasis. Current Tumour Node Metastasis (TNM) staging includes horizontal tumour size, involvement of extradermal structures, and degree of differentiation. The aim of this study was to prospectively analyse the key factors predicting metastasis and local recurrence in cutaneous SCC.

Methods

We assessed prospectively investigated potential risk factors for metastasis or local recurrence of SCC, previously suggested by retrospective studies and small case series, in 615 white patients. Between Jan 1, 1990, and Dec 31, 2001, all patients underwent surgery for cutaneous SCC with complete histological examination of the three-dimensional excision margins (3D-histology) in one centre. Univariate and multivariate analysis included tumour thickness, horizontal size, body site, histological differentiation, desmoplastic growth, history of multiple SCC, and immunosuppression. Primary endpoints were time to metastasis and time to local recurrence, defined as the time from date of diagnosis of the primary tumour to the date of diagnosis of metastasis or local recurrence, respectively.

Findings

653 patients were enrolled in the study. 38 patients were lost to follow-up leaving 615 assessable patients (median age 73 years [range 27–98]). During a median follow-up period of 43 months (range 1–165), 26 (4%) of 615 patients developed metastases and 20 patients developed local recurrence (3%). Tumours 2·0 mm or less in thickness did not metastasise. Metastases occurred in 12 (4%) of 318 tumours between 2·1 mm and 6·0 mm in thickness, and in 14 (16%) of 90 tumours with a thickness greater than 6·0 mm. On multivariate analysis, key prognostic factors for metastasis were increased tumour thickness (hazard ratio 4·79 [95% CI 2·22–10·36]; p<0·0001), immunosuppression (4·32 [1·62–11·52]; p=0·0035), localisation at the ear (3·61 [1·51–8·67]; p=0·0040), and increased horizontal size (2·22 [1·18–4·15]; p=0·0128). The risk of local recurrence depended on increased tumour thickness (6·03 [2·71–13·43]; p<0·0001) and desmoplasia (16·11 [6·57–39·49]; p<0·0001).

Interpretation

Only SCC greater than 2·0 mm in thickness are associated with a significant risk of metastasis. Tumours greater than 6·0 mm are associated with a high risk of metastasis and local recurrence. Desmoplastic growth is an independent risk factor for local recurrence. Studies should assess the role of follow-up visits and sentinel-lymph-node biopsy in high-risk patients.

Funding

This study was supported by the German Research Foundation/Sonderforschungsbereich 685 and Deutsche Krebshilfe (MR), the intramural Angewandte Klinische Forschung fellowship (203-1-0) from the University Medical School, Eberhard Karls University Tuebingen (KDB), and the ‘Südwestdeutsche Tumorzentrum’—Comprehensive Cancer Centre Tübingen (KDB, MR, HB).

Introduction

Cutaneous squamous-cell carcinomas (SCC) have an incidence of 16 per 100 000 people in central Europe1, 2 and of 356 per 100 000 sun-exposed white men in the south of the USA.3 SCC are among the most common malignancies capable of metastasis. Recipients of a solid-organ transplant have a 65-times to 250-times increased risk of SCC compared with the general population4, 5, 6 and a high risk of metastasis.7 The risk of developing SCC seems to depend on the lifetime accumulation of ultraviolet (UV) radiation damage and the extent of immune suppression.

Current data show that SCC in immune-compromised patients have an increased risk of metastasis.7 However, the key factors determining the risk of metastasis or local recurrence remain unclear. Within the current Tumour Node Metastasis (TNM) classification of non-melanoma skin cancers by the American Joint Committee on Cancer (AJCC) and the International Union Against Cancer (UICC), the primary tumour is characterised by horizontal size and Broders' histological degree of differentiation.8, 9 According to this staging system, T1 tumours are 20 mm or less in diameter, T2 tumours are greater than 20 mm but no greater than 50 mm, and T3 tumours are greater than 50 mm in diameter. Depth of invasion is only considered when extradermal structures are affected (T4). However, many other characteristics, such as tumour thickness, certain localisations, or the desmoplastic histological subtype, have also been suggested as prognostic factors.2, 10, 11, 12, 13, 14, 15, 16, 17, 18 Therefore, we did a prospective study to establish the key prognostic factors of SCC by multivariate analysis.

Section snippets

Patients and procedures

Dermatologists and general practitioners, mainly from the southwest of Germany, referred an unselected, representative patient population diagnosed with SCC to the Department of Dermatology (Eberhard Karls University, Tübingen, Germany). All white patients who underwent surgery for SCC between Jan 1, 1990, and Dec 31, 2001 were eligible for the study. SCC of all body sites were included in the study. Exclusion criteria included patients with SCC in situ (eg, Bowen's disease, actinic keratosis,

Results

653 patients were enrolled in the study. Of these, 615 patients had at least one follow-up examination either by a staff member or an external physician and 38 patients were lost to follow-up. Of the 615 assessable patients (table 1), 388 were men (63%). Mean age was 72 years (SD 12; median 73 [range 27–98]). The median and mean follow-up periods were both 43 months (SD 32; range 1–165). No relevant associations between the candidate predictors were noted except a medium correlation between

Discussion

On the basis of data from a previous study14 we analysed prospectively the risk factors associated with SCC, including the TNM criteria, tumour thickness, desmoplastic growth, tumour site, and multiple SCC. Multivariate analysis of this mainly immunocompetent population showed tumour thickness, immunosuppression, localisation at the ear,13 and horizontal size13, 27, 28, 29 as independent parameters determining the risk of metastasis in cutaneous SCC. Tumour thickness and desmoplasia

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