Risk Factors for Cutaneous Squamous Cell Carcinoma Outcomes: A Systematic Review and Meta-analysis

Abstract

Importance

Magnitude of association and quality of evidence for cutaneous squamous cell carcinoma (cSCC) and risk factors for outcomes have not been reviewed and analyzed systematically.

Objective

Review and systematically analyze all published data on risk factors for recurrence, metastasis, and disease-specific death (DSD) of cSCC.

Data Sources

Comprehensive medical literature search from each database’s inception to May 14, 2015.

Study Selection

Inclusion criteria were studies with ≥10 patients, comparative data for ≥1 cSCC risk factors, and an outcome of interest. Exclusion criteria were noncutaneous squamous cell carcinoma (SCC), anogenital SCC, inability to extract cSCC data from other malignancy data, SCC in situ, Marjolin tumor, and genetic disorders predisposing to cSCC.

Data Extraction and Synthesis

Two reviewers independently abstracted the data. Meta-analysis used the random effects model. Risk of bias was assessed through Newcastle-Ottawa Scale.

Main Outcomes and Measures

A priori outcomes were recurrence, metastasis, and DSD.

Results

Thirty-six studies (17,248 patients with 23,421 cSCCs) were included. Statistically significant risk factors for recurrence were Breslow >2 mm (risk ratio [RR] [95% CI], 9.64 [1.30–71.52]), invasion beyond subcutaneous fat (7.61 [4.17–13.88]), Breslow >6 mm (7.13 [3.04–16.72]), perineural invasion (PNI) (4.30 [2.80–6.60]), diameter >20 mm (3.22 [1.91–5.45]), location on temple (3.20 [1.12–9.15]), and poor differentiation (2.66 [1.72–4.14]). Statistically significant risk factors for metastasis were invasion beyond subcutaneous fat (RR [95% CI], 11.21 [3.59–34.97]); Breslow >2 mm (10.76 [2.55–45.31]); Breslow >6 mm (6.93 [4.02–11.94]); diameter >20 mm (6.15 [3.56– 10.65]); poor differentiation (4.98 [3.30–7.49]); PNI (2.95 [2.31–3.75]); location on temple (2.82 [1.72–4.63]), ear (2.33 [1.67–3.23), and lip (RR [1.54–3.37]); and immunosuppression (1.59 [1.07–2.37]). Factors for DSD were diameter >20 mm (RR [95% CI], 19.10 [5.80–62.95]), poor differentiation (5.65 [1.76–18.20]), location on ear (4.67 [1.28–17.12]) and lip (4.55 [1.41–14.69]), invasion beyond subcutaneous fat (4.49 [2.05–9.82]), and PNI (4.06 [3.10–5.32]). Evidence quality was considered low to moderate.

Conclusions and Relevance

Tumor depth is associated with highest RR of local recurrence and metastasis of cSCC; tumor diameter ≥20 mm is associated with highest risk of DSD. Unified, consistent collection and reporting of risk factors in a prospective, multicentered effort are needed to further understand the increasing cSCC.

Grade of Evidence

2A. Quality of Evidence: Level B.

Introduction

Cutaneous squamous cell carcinoma (cSCC) is the second most common malignancy of the skin, with an estimated annual incidence of 700,000 in the United States.^1,2 Most cases of cSCC portend an excellent prognosis following surgical removal.³ However, 3.7% to 5.2% of patients have nodal metastasis and 1.5% to 2.1% die of cSCC.^4–8 Although these rates are relatively low compared with many other malignancies, the absolute number of cSCC patients who have nodal metastasis is estimated at 5,604 to 12,572 in the United States alone.¹ Furthermore, the absolute number of cSCC-related deaths is estimated between 3,932 to 8,791 annually, the upper limit of which approaches annual melanoma-related deaths.¹ The absence of a national tumor registry for cSCC complicates the analysis of prognostic factors related to outcomes on a broad scale. Thus, the current understanding of prognostic factors is based primarily on retrospective analyses of single-institution cohorts with heterogeneously reported data. The purpose of the present study was to perform a systematic review and meta-analysis of all published reports of cSCC risk factors and outcomes, to quantify the magnitude of each risk factor and the quality of the supporting data.

Methods

The study was deemed exempt by the Mayo Clinic Institutional Review Board.

Literature Search

A comprehensive and systematic search of Ovid Medline In-Process and Other Non-Indexed Citations, MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, and Scopus was performed from each database’s earliest inception to May 14, 2015, by an experienced librarian (L.J.P.), with input from the study’s principle investigator (C.L.B.) and lead author (A.K.T.). Controlled vocabulary supplemented with keywords was used to search for studies of risk factors in cSCC and association with outcomes. The search strategy is outlined in eTable (online supplement). Bibliographies of selected review articles were reviewed for additional relevant studies. Only studies on human data, published or translated into English, were included.

Eligibility Criteria

Inclusion criteria were studies of ≥10 patients with cSCC that reported comparative data associating at least 1 defined risk factor (ie, depth of invasion; perineural invasion [PNI]; diameter; location on lip, ear, temple, or cheek; tumor differentiation; and immunosuppression) and an outcome of interest (ie, recurrence, nodal metastasis, and disease-specific death [DSD]).

Exclusion criteria for the studies included any of the following: squamous cell carcinoma (SCC) in situ, noncutaneous SCC, anogenital SCC, cSCC data that could not be extracted from data on other malignancies (eg, basal cell carcinoma, melanoma), cSCC in patients with genetic disorders that predispose to cSCC (eg, xeroderma pigmentosa), cSCC arising in scar tissue (Marjolin tumor), and an outcome of interest present at study initiation. No limitations were imposed on the basis of treatment modality.

Data Abstraction

Two reviewers (A.K.T. and B.F.K.) independently selected studies on the basis of inclusion and exclusion criteria. Disparities in selection were resolved through discussion and ultimately by a third reviewer (C.L.B.). Studies were initially reviewed on the basis of title and abstract; those deemed relevant were reviewed in full text to establish the final set of studies ultimately included. In cases of study duplicity, the more recent and complete studies were selected for inclusion. From these studies, data were abstracted in duplicate (A.K.T. and B.F.K.) to verify accuracy.

Risk of Bias Assessment

Risk of bias assessment was analyzed for each article by 2 investigators (A.K.T. and B.F.K.) using the Newcastle-Ottawa Scale.⁹ We considered that the most important factor in determining the risk of bias was the ability of a study to adjust for confounders (ie, other risk factors) using multivariate adjustment.

Statistical Analysis

From each study, we extracted or estimated the risk ratio (RR) (presented as hazard ratio [HR] or odds ratio [OR]) for each risk factor and outcome of interest, with 95% CI. Various association measures were assumed to be comparable statistically. Multivariate estimates were preferentially extracted when available. Meta-analysis was performed with the random effects model,¹⁰ reporting RR (95% CI). The I² statistic¹¹ also was calculated to measure inconsistency; a value >50% implied substantial heterogeneity (ie, difference in the estimates derived from each study). Forest plots were constructed for all associations of risk factor and outcome. Analysis was conducted through statistical software (Comprehensive Meta-Analysis, Version 3.0; Biostat).

Results

Literature Search

Database search identified 1,156 publications and meeting abstracts. After initial review of abstracts and titles, 1,034 records were excluded (Figure 1). The other 122 studies were reviewed in full text, and ultimately, 36 studies were included in our analysis.

Figure 1.

Flow Diagram of Preferred Reporting Items for Systematic Reviews and Meta-analyses for the Systematic Literature Search. RF indicates risk factor.

Study Characteristics and Meta-analysis

The 36 studies described 23,421 cSCCs in 17,248 patients; 5 were prospective cohort studies and 31 were retrospective studies. No randomized trials were identified. The number of patients in the included studies ranged from 41 to 6,164 (Table 1).

Table 1.

Study Characteristics

First Author, Year	Study Years	Location	Study Type	No. of Patients	No. of cSCCs	RF Addressed	Outcomes	Inclusion Criteria	Follow-up Data
Dinehart and Pollack, 198912	1979–1988	North Carolina, single institution	Retrospective cohort of consecutive cSCC	365	365	Location	Metastasis	Biopsy-proven cSCC; treated with Mohs	Mean (range), 1.7 y (2 mo–7.8 y)
Dormand et al, 201013	1997–2004	United Kingdom, single institution	Retrospective cohort of limb cSCC	243	517	Differentiation	Metastasis	Biopsy-proven cSCC; extremities only	Mean (range), 6.2 (4–22) y
Goepfert et al, 198414	1970–1979	Texas, single institution	Retrospective cohort of consecutive cSCC	520	967	PNI	Recurrence, metastasis, DSD	Biopsy-proven cSCC	98% of patients had minimum follow- up of 2 y
Quaedvlieg et al, 200615	1982–2002	Netherlands, single institution	Retrospective case-control of metastatic cSCC	580	915	Differentiation, PNI, location	Metatasis	Using PALGA registry in Netherlands; contained all registered cSCC in University Hospital; biopsy proven	At least 3 y of follow-up; mean (range), 5.7 (0.25–21) y
Brantsch et al, 20084	1990–2001	Germany, single institution	Prospective cohort of cSCC	615	615	Depth, diameter, location, differentiation, immunosuppression	Recurrence, metastasis	Biopsy-proven cSCC	Median (range), 43 (1–165) mo
Brinkman et al, 201416	2001–2008	Netherlands, single institution	Retrospective cohort of cSCC	131	155	Differentiation	Metastasis, DSD	Biopsy-proven cSCC; treated with surgical excision	Median (range), 81 (27–125) mo
Brougham et al, 20125	1997–2007	New Zealand, regional NMSC database	Retrospective cohort of cSCC	6,164	8,997	Location, PNI, differentiation	Metastasis	Biopsy-proven cSCC	Minimum, 30-mo follow-up; mean (SD) 71 (25) mo; median (range), 70 (31–121) mo
Eroğlu et al, 199617	1980–1989	Turkey, single institution	Retrospective cohort of cSCC	1,039	1,039	Location, diameter, differentiation	Recurrence	Biopsy-proven cSCC	Median (range), 28 (6–149) mo
Faustina et al, 200418	1952–2000	Texas, single institution	Retrospective cohort of periocular cSCC	111	111	PNI	Metastasis	Biopsy-proven cSCC; periocular only	Median (range), 76.6 (6–484) mo
Gonzalez et al, 201419	1990–2012	Argentina, single institution	Retrospective cohort of head/neck cSCC	434	434	Location, diameter, differentiation	Recurrence, metastasis	Biopsy-proven cSCC; treated with Mohs	Mean (range), 56.9 (10–251) mo
Griffiths et al, 200220	1990–1995	United Kingdom, single institution	Retrospective cohort of consecutive cSCC	157	157	Location	Metastasis, DSD	Biopsy-proven cSCC	93 patients had 5-y follow-up
Pugliano-Mauro et al, 201021	1996–2006	Vermont, single institution	Retrospective cohort of high- risk cSCC	215	260	Location, PNI	Metastasis	Biopsy-proven high- risk cSCC, including recurrent tumors; treated with Mohs	Mean, 3.9 y
Immerman et al, 198322	1970–1980	Illinois, single institution	Retrospective cohort of consecutive cSCC	86	86	Differentiation	Recurrence	Biopsy-proven cSCC	Mean (range), 4.5 y (6 mo–10 y)
Karia et al, 20146	2000–2009	Massachusetts, single institution	Retrospective cohort of consecutive cSCC	974	1,818	Location, diameter, depth, differentiation, immunosuppression	Recurrence, metastasis, DSD	Biopsy-proven cSCC; excluded SCCIS, recurrent SCC, eyelid/anogenital SCC	Median (range), 50 (2–142) mo
Mehrany et al, 200523	1988–1999	Minnesota, single institution	Retrospective case-control of cSCC in CLL patients	142	171	Differentiation, immunosuppression	Recurrence	Biopsy-proven cSCC; treated with Mohs	Mean, 3.3 y; median (range), 2.6 (0.04–13.7) y
Metchnikoff et al, 201224	2001–2010	California, single institution	Retrospective cohort of consecutive cSCC in heart/lung transplant recipients	41	225	Diameter, differentiation, PNI	Recurrence	Biopsy-proven cSCC in heart/lung transplant recipients	Median (range), 15.2 mo (6 d–9 y)
Moore et al, 200525	1996–2001	Texas, single institution	Prospective cohort of head and neck cSCC	193	193	Location, differentiation, depth, PNI	Metastasis	Biopsy-proven head/neck cSCC	Median (range), 20 (3.3–70) mo
Mourouzis et al, 20097	2000–2002	United Kingdom, single institution	Retrospective cohort of cSCC	194	218	Location, differentiation	Metastasis	Biopsy-proven cSCC of the head and neck; treated with excision	Monitored for 3 y; range, 30–60 mo
Mullen et al, 200626	1994–2004	Texas, single institution	Retrospective cohort of trunk/extremity cSCC	136	149	Diameter, differentiation	Recurrence	Biopsy-proven cSCC	Median, 2.4 y
Peat et al, 201227	1996–2001	New Zealand, single institution	Retrospective case control of cSCC	170	170	Differentiation, PNI	Metastasis	Biopsy-proven cSCC	Follow-up, 5 y
Schmults et al, 20138	2000–2009	Massachusetts, single institution	Retrospective cohort of consecutive cSCC	985	1,832	Location, PNI	Recurrence, metastasis, DSD	Biopsy-proven cSCC; excluded SCCIS, recurrent SCC	Median (range), 50 (2–142) mo
Toll et al, 201228	2001–2010	Spain, 6 tertiary care hospitals	Retrospective case control of cSCC	101	101	Differentiation, PNI	Metastasis	Biopsy-proven cSCC; metastatic group vs nonmetastatic control group	Mean, 24 mo
Baker et al, 200129	1990–1995	United Kingdom, single institution	Retrospective cohort of head/neck cSCC	183	227	Location	Regional metastasis	Biopsy-proven cSCC	Minimum follow- up, 2 y
Cherpelis et al, 200230	1988–1998	South Carolina, single institution	Retrospective cohort of cSCC	200	200	Location, diameter, differentiation, PNI	Metastasis	Biopsy-proven cSCC; treated with Mohs	Range, 6 mo–10 y
Clayman et al, 200531	1996–2001	Texas, single institution	Prospective cohort of cSCC	210	277	Depth, PNI	DSD	Biopsy-proven cSCC	Median (range), 22 (2–72) mo
Kyrgidis et al, 201032	1996–2006	Greece, single institution	Prospective cohort of head/neck cSCC	315	315	Depth, differentiation, PNI	DSD	Biopsy-proven cSCC	Mean (range), 46.7 (12–124) mo
Leibovitch et al, 200533	1993–2002	Australia, multicenter	Prospective cohort of cSCC with PNI	1,177	1,177	PNI	Recurrence	Biopsy-proven cSCC; treated with Mohs	621 patients were lost to follow-up; 5-y follow-up
Roozeboom et al, 201334	2005–2007	Netherlands, single institution	Retrospective cohort of consecutive cSCC	224	224	Location, depth, differentiation, PNI	Recurrence, metastasis	Biopsy-proven cSCC	Median (range), 43 (0–73) mo
Pereira and Morgado, 199435	1983–1993	Portugal, single institution	Retrospective cohort of cSCC	43	43	Diameter	Recurrence	Biopsy-proven cSCC; treated with ED&C followed by cryotherapy	Minimum follow- up, 4 y
Harwood et al, 200636	1995–1997	United Kingdom, single institution	Retrospective case control of cSCC in OTR	65	100	Immunosuppression	Recurrence, metastasis	Biopsy-proven primary cSCC; immunocompromised group (OTR) with immunocompetent control group	Follow-up,10 y
Friedman et al, 198537	1965–1975	Virginia, single institution	Retrospective cohort of cSCC	63	71	Depth, differentiation	Recurrence, DSD	Biopsy-proven cSCC	Range, 8–18 y
Breuninger et al, 199038	Not specified	Germany, single institution	Retrospective cohort of cSCC	571	673	Location, diameter, differentiation, depth	Metastasis	Biopsy-proven cSCC	Mean (range), 6 (1- 12) y
Krediet et al, 201539	2005–2009	Germany, single institution	Retrospective cohort of consecutive cSCC	143	143	Location, diameter, differentiation, immunosuppression	Recurrence, metastasis	Biopsy-proven cSCC treated with excision	Minimum, 24 mo
Wermker et al, 201540	2005–2011	Germany, single institution	Retrospective cohort of consecutive cSCC of ear	353	353	Diameter, depth, differentiation, PNI, immunosuppression	Metastasis	Biopsy-proven cSCC of external ear; treated surgically	Minimum, 6 mo; mean (range), 43.3 (6–98) mo
Vasconcelos et al, 201441	1999–2003	Brazil, single institution	Retrospective cohort of head/neck cSCC	61	79	Differentiation, PNI	Recurrence	Biopsy-proven cSCC of head/neck; treated surgically	Median (range), 5 (2–7) y
Stein and Tahan, 199442	1960–1991	Massachusetts, single institution	Retrospective cohort of lip cSCC	44	44	Differentiation, depth	Metastasis	Biopsy-proven cSCC of lip	Median (range), 53 (5–212) mo

Abbreviations: CLL, chronic lymphocytic leukemia; cSCC, cutaneous squamous cell carcinoma; DSD, disease-specific death; ED&C, electrodesiccation and curettage; Mohs, Mohs micrographic surgery; OTR, organ transplant recipient; PALGA, Pathological Anatomy National Automated Archive; PNI, perineural invasion; SCC, squamous cell carcinoma; SCCIS, squamous cell carcinoma in situ.

Analyzed risk factors and their respective associations with outcomes of recurrence, metastasis, and DSD are outlined in Figure 2, with corresponding RRs, 95% CIs, P values, I² statistics, and forest plot. Risk factors associated with statistically significant increased risk of recurrence were Breslow >2 mm (RR [95% CI], 9.64 [1.30– 71.52]), invasion beyond subcutaneous fat (RR [95% CI], 7.61 [4.17–13.88]), Breslow >6 mm (RR [95% CI], 7.13 [3.04–16.72]), presence of PNI (RR [95% CI], 4.30 [2.80–6.60]), diameter >20 mm (RR [95% CI], 3.22 [1.91–5.45]), location on the temple (RR [95% CI], 3.20 [1.12–9.15]), and poor differentiation (RR [95% CI], 2.66 [1.72–4.14]).

Figure 2.

Summary of Risk Factors and Outcome Associations for cSCC. cSCC indicates cutaneous squamous cell carcinoma; PNI, perineural invasion.

Statistically significant risk factors for metastasis were invasion beyond subcutaneous fat (RR [95% CI], 11.21 [3.59–34.97]); Breslow >2 mm (RR [95% CI], 10.76 [2.55–45.31]); Breslow >6 mm (RR [95% CI], 6.93 [4.02–11.94]); diameter >20 mm (RR [95% CI], 6.15 [3.56–10.65]); poor differentiation (RR [95% CI], 4.98 [3.30– 7.49]); presence of PNI (RR [95% CI], 2.95 [2.31–3.75]); location on the temple (RR [95% CI], 2.82 [1.72–4.63]), ear (RR [95% CI], 2.33 [1.67–3.23]), and lip (RR [95% CI], 2.28 [1.54–3.37]); and immunosuppression (RR [95% CI], 1.59 [1.07–2.37]).

Several of the risk factors showed statistically significant association with DSD: diameter >20 mm (RR [95% CI], 19.10 [5.80–62.95]), poor differentiation (RR [95% CI], 5.65 [1.76–18.20]), location on the ear (RR [95% CI], 4.67 [1.28–17.12]) and lip (RR [95% CI], 4.55 [1.41–14.69]), invasion beyond subcutaneous fat (RR [95% CI], 4.49 [2.05–9.82]), and presence of PNI (RR [95% CI], 4.06 [3.10–5.32]).

Study Quality

Scores from the Newcastle-Ottawa Scale are provided in Table 2, with risk assessments for each study. Six studies (16.7%) were deemed to have low risk of bias due to presence of multivariate data; the other 30 studies were of high or unclear risk due to lack of adjustment for confounding variables. The number of studies for each risk factor ranged from 1 to 15. Risk factor and outcome associations are outlined in Figure 2, which visually depicts them in a forest plot.

Table 2.

Newcastle-Ottawa Scale^a Scoring of Studies in the Meta-analysis

Author, Year	Study Type	Selection	Comparability	Exposure/ Outcome	Assessment of Risk
Dinehart and Pollack, 198912	Cohort of consecutive SCC cases	***	**	**	High/unclear
Dormand et al, 201013	Cohort of limb SCC cases	***	*	***	High/unclear
Goepfert et al, 198414	Cohort of consecutive SCC cases	****	*	***	High/unclear
Quaedvlieg et al, 200615	Case control of metastatic SCC	****	*	**	High/unclear
Brantsch et al, 20084	Cohort of SCC cases (prospective)	****	**	***	High/unclear
Brinkman et al, 201416	Cohort of SCC cases	****	*	***	Low
Brougham et al, 20125	Cohort of SCC cases	****	**	**	Low
Eroğlu et al, 199617	Cohort of SCC cases	***	**	***	High/unclear
Faustina et al, 200418	Cohort of periocular SCC cases	***	*	**	High/unclear
Griffiths et al, 200220	Cohort of consecutive SCC cases	****	**	***	High/unclear
Pugliano-Mauro et al, 201021	Cohort of high-risk SCC cases	***	*	***	High/unclear
Immerman et al, 198322	Cohort of consecutive SCC cases	****	**	***	High/unclear
Karia et al, 20146	Cohort of consecutive SCC cases	****	**	***	Low
Mehrany et al, 200523	Case control	****	**	**	High/unclear
Metchnikoff et al, 201224	Cohort of consecutive heart/lung transplant SCC	****	**	**	High/unclear
Moore et al, 200525	Cohort of SCC (prospective)	***	*	**	High/unclear
Mourouzis et al, 20097	Cohort of excised SCC	****	**	**	High/unclear
Mullen et al, 200626	Cohort of trunk/extremity SCC	****	**	***	High/unclear
Peat et al, 201227	Case control	****	**	***	High/unclear
Schmults et al, 20138	Cohort of SCC cases	****	**	***	Low
Toll et al, 201228	Case control	****	**	***	Low
Baker et al, 200129	Cohort of SCC	****	**	**	High/unclear
Cherpelis et al, 200230	Cohort of SCC	****	**	**	High/unclear
Clayman et al, 200531	Cohort of SCC (prospective)	****	**	**	High/unclear
Kyrgidis et al, 201032	Cohort of consecutive SCC cases (prospective)	****	**	***	High/unclear
Leibovitch et al, 200533	Cohort of PNI (prospective)	***	*	**	High/unclear
Roozeboom et al, 201334	Cohort of consecutive SCC cases	****	**	**	High/unclear
Pereira and Morgado, 199435	Cohort of SCC	***	*	*	High/unclear
Harwood et al, 200636	Case control of cSCC in organ transplant recipients	****	*	**	High/unclear
Friedman et al, 198537	Cohort of SCC	****	**	***	High/unclear
Breuninger et al, 199038	Cohort of SCC	****	**	**	High/unclear
Gonzalez et al, 201419	Cohort of consecutive head/neck SCC cases	***	*	***	Low
Krediet et al, 201539	Cohort of consecutive cSCC	****	**	**	High/unclear
Wermker et al, 201540	Cohort of consecutive cSCC of ear	****	*	***	High/unclear
Vasconcelos et al, 201441	Cohort of head/neck cSCC	****	**	***	High/unclear
Stein and Tahan, 199442	Cohort of cSCC of lip	****	*	***	High/unclear

Abbreviations: cSCC, cutaneous squamous cell carcinoma; PNI, perineural invasion; SCC, squamous cell carcinoma.

^aPossible scores are 0–4 asterisks for selection, 0–2 asterisks for comparability, and 0–3 asterisks for exposure/outcome, regarding risk of bias,

^*with indicating a low score

^****indicating the highest score.

Discussion

The meta-analysis of these data provides a quantitative value for each risk factor–outcome association. The pooled data for the majority of these risk factors showed a statistically significant association with the outcomes of interest; however, some previously reported risk factors for each outcome did not have a statistically significant association. Since the publication of the frequently cited report of cSCC outcomes by Rowe et al⁴³ in 1992, several other studies have contributed to this body of knowledge. Most recently, staging systems have been proposed for the purpose of stratifying patients by outcomes. These include the American Joint Committee on Cancer (AJCC), Seventh Edition,⁴⁴ Union for International Cancer Control (UICC),⁴⁵ and Brigham and Women’s Hospital (BWH) staging systems,⁴⁶ summarized in Table 3. Although the BWH system was developed on the basis of a single institution’s experience, the AJCC and UICC are based on expert consensus. The present meta-analysis summarizes the entire body of data on these previously reported risk factors. Therefore, our data provide, to our knowledge, the most comprehensive review of previously reported risk factors for cSCC related to outcomes of local recurrence, metastasis, and DSD.

Table 3.

Summary of the AJCC, UICC, and BWH Tumor (T) Staging Systems

Tumor Staging System	Definition
AJCC
T1	Tumor ≤2 cm in greatest dimension, with <2 high-risk factorsa
T2	Tumor >2 cm in greatest dimension or with ≥2 high-risk factorsa
T3	Tumor with invasion of orbit, maxilla, mandible, or temporal bones
T4	Tumor with invasion of other bones or direct perineural invasion of skull base
UICC
T1	Tumor ≤2 cm in greatest dimension
T2	Tumor >2 cm in greatest dimension
T3	Tumor with invasion of deep structures (eg, muscle, cartilage, bone [excluding axial skeleton], orbit)
T4	Tumor with invasion of axial skeleton or direct perineural invasion of skull base
BWH
T1	0 high-risk factorsb
T2a	1 high-risk factor
T2b	2–3 high-risk factors
T3	≥4 high-risk factors or bone invasion

Abbreviations: AJCC, American Joint Committee on Cancer; BWH, Brigham and Women’s Hospital; T, tumor stage from TNM staging system; UICC, International Union Against Cancer.

^aAJCC high-risk factors include >2 mm thickness, Clark level ≥IV, perineural invasion, primary site ear, primary site non-hair-bearing lip, or poorly differentiated histology.

^bBWH high-risk factors include tumor diameter ≥2 cm, poorly differentiated histologic findings, perineural invasion ≥0.1 mm, and tumor invasion beyond fat (excluding bone invasion, which automatically upgrades tumor to BWH T3).

Adapted from Karia et al.⁶ Used with permission.

Local Recurrence

Optimal management of cSCC is predicated on local tumor control because local recurrence is often the first indicator of aggressive biologic behavior.^3,47 In our analysis, tumor depth, recorded as Breslow thickness (mm) or anatomic depth, was associated with the greatest RR of local recurrence. The highest-quality comparative data on Breslow depth was from Brantsch et al,⁴ one of the few prospective datasets in this analysis. The staging system reported in the AJCC Seventh Edition,⁴⁴ for cSCC includes both Breslow depth >2 mm and Clark level ≥4 as high-risk characteristics. Meanwhile, the largest dataset describing anatomic depth was a retrospective analysis by Karia et al.⁶ In that study, depth was measured by anatomic depth rather than Breslow depth, with tumor depth beyond subcutaneous fat considered a high-risk characteristic. Although it is reassuring that the significance of tumor depth is verified through distinct methods of measure, the absence of a uniform measure and reporting together contribute to data heterogeneity and ambiguity for the clinician.

The theoretical advantage of Breslow depth measurement is the ability to perform refined analysis of data on a continuous numerical variable. From a practical perspective, however, measurement of Breslow depth is limited by time and the abundant frequency of transected shave biopsy specimens. Defining depth on the basis of the anatomic depth, such as an invasion beyond subcutaneous fat, simplifies the objective measure assessed in both horizontally and vertically sectioned tissue specimens. If adopted as a standard, the parameters for relation to anatomic structures, such as depth/invasion beyond subcutaneous fat, will require strict unambiguous definition.

PNI was associated with the greatest RR of local recurrence after tumor depth. As with tumor depth, the reporting of PNI was also heterogeneous. Several articles reported PNI as a binary variable, whereas others^6,48 also analyzed on the basis of the diameter of the involved nerve. For the purpose of the present study, PNI was analyzed as a binary variable, including 6 articles, and was associated with an RR of local recurrence (RR [95% CI], 4.30 [2.80–6.60]; P <.01).^{8,14,24,33,34,41} A report by Karia et al⁶ also indicated that the RR increases with the size of the involved nerve, with RR (95% CI) of regional recurrence for nerves <0.1 mm in diameter of 5.6 (2.0–15.9) (P=.001) compared with nerves ≥0.1 mm in diameter (RR [95% CI], 10.4 [4.4–24.7]; P<.001). Interestingly, the AJCC Seventh Edition staging system for cSCC⁴⁴ includes PNI as a binary variable for high risk, whereas the BWH staging system includes PNI as a risk factor when the involved nerve is ≥0.1 mm in diameter. As with tumor depth, the uniform definition and reporting of PNI are areas of critical need.

In descending order of RR, tumor diameter, location on the temple, and poor differentiation were associated with local recurrence. A cutoff of 20 mm was used for tumor diameter since it is uniformly included in the AJCC Seventh Edition staging system, the UICC staging system, and the BWH staging system. Although 4 studies in the analysis did show statistical significance,^6,17,24,35 the prospective data from Brantsch et al⁴ did not find an association between diameter and recurrence on multivariate analysis; however, a statistically significant increase in risk was noted on univariate analysis (HR [95% CI], 3.47 [1.89–6.39]; P<.0001). Tumor location on the temple, although not part of the AJCC, UICC, or BWH staging system,⁴⁴ was associated with a higher risk of recurrence (RR [95% CI], 3.20 [1.1–9.0]; P=.03) than tumor location on either lip or ear, albeit this finding was based on a single, but relatively large, retrospective analysis by Schmults et al.⁸ Poor differentiation also was found to have statistically significant association with recurrence (RR [95% CI], 2.66 [1.72–4.14]; P<.01), based on pooled data from 11 studies.^{4,6,17,19,22–24,34,37,39,41}

Surprisingly, location on the lip or ear and immunosuppression were not associated with a statistically significant RR of local recurrence in the present meta-analysis. The lip⁴³ and ear^6,43 have been reported as risk factors in some studies; however, a sufficient body of data suggests otherwise.^4,17,34 Interestingly, both the lip and the ear are included in the AJCC system but not in the UICC and BWH systems. Immunosuppression is a notable item within AJCC but is not included in the staging system, and it is not part of the BWH or UICC staging system.

For the purposes of the present analysis, immunosuppression was included as a general category without further stratification. Although immunosuppression was associated with recurrence in the prospective data by Brantsch et al⁴ and in certain subsets of well-defined patients, such as those with chronic lymphocytic leukemia,²³ the results of these 2 studies were likely offset by other reports that did not stratify on the basis of the type of immunosuppression.^6,34,39 Taken together, the data suggest that clarification of the nature of the immunosuppression is critical for understanding the factors that influence local recurrence. Notably, the I² for location on the lip or the ear and for immunosuppression were increased at 52%, 59%, and 39%, respectively, indicating substantial data inconsistency, which also could contribute to a lack of statistical significance.

Metastasis

The correlation between cSCC risk factors and metastasis was the most well studied and well represented in our meta-analysis. The implications of metastasis are obvious since they generally are associated with poor outcomes.^8,49,50 Thus, identifying risk factors associated with metastasis in cSCC is crucial for proper staging and for early identification of high-risk patients. As with local recurrence, tumor depth was associated with the highest RR of metastasis, our study showed, regardless of whether depth is measured as Breslow thickness or anatomic depth. These results are based on a total of 7 studies,^{4,6,25,34,38,40,42} one of which presents data on both Breslow depth and anatomic depth.³⁸ Interestingly, the RR for metastasis in our analysis was greater for Breslow >2 mm than for Breslow >6 mm. This finding may reflect the absolute number of patients in the studies who had nodal metastases with primary tumor depths of 2 to 6 mm vs the smaller population of patients with the same outcome and a tumor depth >6 mm. Of importance, no patients in the prospective data from Brantsch et al⁴ had nodal metastasis with a Breslow depth <2 mm. The BWH group found that the anatomic depth associated with metastasis was the depth beyond subcutaneous fat (RR [95%CI], 7.0 [2.4–20.3]; P<.001).⁶ The practice gaps related to the reporting of depth hold true for association with metastasis and association with local recurrence.

Tumor diameter >20 mm and poor differentiation were associated with similar RRs of 6.15 (95% CI, 3.56–10.65) and 4.98 (95% CI, 3.30–7.49), respectively, for developing metastasis. A total of 8 included studies were based on tumor diameter and metastasis.^{4,6,19,26,30,38–40} Interestingly, the poorly differentiated cSCC and metastasis were the most well-studied association in this analysis, with a total of 18 publications that provided comparative data.^{4–7,13,15,16,19,25–28,30,34,38–40,42}

The remaining risk factors associated with increased RR of metastasis in this analysis were PNI (RR [95% CI], 2.95 [2.31–3.75]), location on the temple (2.82 [1.72– 4.63]), location on the ear (2.33 [1.67–3.23]), location on the lip (2.28 [1.54–3.37]), and immunosuppression (1.59 [1.07–2.37]). The relative absence of heterogeneity for these risk factors is reflected in the I² values of 0%, 6%, 27%, and 0% for location on the temple, ear, and lip and immunosuppression, respectively. It further underscores the association between these risk factors and metastasis. Tumor localization on the temple is not included as a risk factor in the AJCC, UICC, and BWH staging systems. Yet, these results suggest that it might be advisable to categorize this location with the other high-risk anatomic locations, such as ear and lip. Furthermore, a more stratified approach to the specific type of immunosuppression (eg, human immunodeficiency virus infection, solid-organ transplant, chronic lymphocytic leukemia) would afford greater precision in our risk analysis for metastasis in these patients.

Disease-Specific Death

Of all the outcomes, DSD had the least amount of comparative data available for analysis. The risk factor with the highest RR for DSD was a diameter >20 mm (RR [95% CI], 19.10 [5.80–62.95]). However, this conclusion is based solely on 1 study by Karia et al.⁶ Poor differentiation, location on the ear or the lip, invasion beyond subcutaneous fat, and PNI were associated with a statistically significant increase ranging from 4- to 6-fold, in the RR of DSD. Tumor depth, though significant, was not as highly associated with DSD as with local recurrence and metastasis—likely, a reflection of a paucity of data and the heterogeneity of available studies, reflected in the I² of 76%. PNI as a risk factor for DSD had an I² of 0%, reinforcing this association. The single report with the largest dataset related to DSD was from Karia et al.⁶ In their multivariate analysis, the risk factors with the greatest association to DSD were diameter >20 mm (HR [95% CI], 19.1 [5.8–63.0]; P<.001), invasion beyond subcutaneous fat (HR [95% CI], 11.1 [3.4–35.8]; P<.001), location on the ear (HR [95% CI], 10.1 [1.8–57.0]; P=.008), and poor differentiation (HR [95% CI], 10.0 [3.4–28.9]; P<.001). Only a single study that reported immunosuppression of 143 patients as a risk factor for DSD was included in our analysis, and the authors of that report acknowledged that their study was underpowered to assess prognostic significance.^6,8 Given the increasing burden of cSCC and the estimated magnitude of DSD, the results of our analysis further emphasize the need for comprehensive reporting of these phenomena.

Limitations

This analysis was limited by several factors. First, it is possible that there were pertinent studies that were not identified because of inherent limitations in database literature searches. Second, the quality of evidence is limited by data largely derived from single-center experiences and retrospective analyses with heterogeneous data reporting and study design. Third, some included studies that had variable and at times limited follow-up data. However, no eligibility criteria were imposed on the basis of follow-up; rather, such limitations were reflected in the Newcastle-Ottawa scoring (Table 2). Fourth, many of the studies provided unadjusted estimates, and many of the risk factors can plausibly be codependent. Fifth, we included studies in which a small proportion of patients had SCC in the setting of scar, genetic disorder, or anogenital region.

Conclusions

This systematic review and meta-analysis study is, to our knowledge, the largest and most comprehensive study of risk factors related to outcomes for cSCC. These results verify the significance of many previously reported factors while providing a novel, robust quantitative risk for each risk factor and the associated outcomes of local recurrence, metastasis, and death. In the short term, these results may help guide clinicians in their risk assessment of patients, particularly patients with only 1 identified risk factor, while keeping in mind the inherent limitations of the data. In the long term, these results may be used to refine the evolving work on staging systems for cSCC while providing a renewed call to action for data collection. Not only are unambiguous definitions for each risk factor needed, but also a comprehensive, uniform reporting of risk factors and outcomes is needed, to provide optimal care for the increasing number of patients with cSCC in the United States and globally.

Abbreviations

AJCC

American Joint Commission of Cancer

BWH

Brigham and Women’s Hospital

cSCC

cutaneous squamous cell carcinoma

DSD

disease-specific death

HR

hazard ratio

OR

odds ratio

PNI

perineural invasion

RR

risk ratio

SCC

squamous cell carcinoma

UICC

Union for International Cancer Control