Author (year of publication)

Level of evidence

Study design

Patients (N)

Inclusion criteria

Follow-up

Outcome measures

Results

Lost to follow-up

Comments

Brantsch (2008)

A2

Prospective

study

653 patients

White patients who underwent surgery for SCC between 1990-2001 (one center in Germany). SCC of all body

sites were included in the study.

Median follow-up of 43 months

(Risk factors for) metastasis and local recurrence ( time to metastasis and time to local recurrence, defi ned as the time from date of diagnosis of the primary tumour to the date of diagnosis of metastasis or local recurrence)

26/615 (4%) patients developed metastases and 20/615 (3%) local recurrence

Tumour thickness

- ≤2.0 mm did not metastasize

- 2.1-6.0 mm: 12/318 (4%) metastases

- >6.0 mm: 14/90 (16%) metastases

Multivariate analysis

Prognostic factors for metastasis:

- increased tumour thickness

(HR 4.79; 95% CI 2.22-10.36; p<0.0001)

- immunosuppression (HR 4.32; CI 1.62-11.52; p=0.0035)

- localisation ear (HR 3.61; CI 1.51-8.67; p=0.0040)

- increased horizontal size (HR 2.22; CI 1.18-4.15; p=0.0128)

For local recurrence:

- increased tumour thickness (HR 6.03; CI 2.71-13.43; p<0.0001)

- desmoplasia (HR 16.11; CI 6.57-39.49; p<0.0001)

38

Breuniger (2012)

B

Prospective single centre studie

615

Primary cSCC

NS

An evaluation was made between the UICC 2009 classification and AJCC 2010 (7^th) classification

Neither classification contains information about prognosis.

The AJCC has introduced

six “high-risk features” to differentiate between T1 and T2. However, this

does not seem reasonable. Only rare cases are classified as T4. Both systems

have different N classifications. A clinical cT classification based on tumor size

2 cm seems reasonable but not sufficient. It should be complemented by a

postoperative p (pathologic) T classification based on tumor thickness: “no risk”

# 2 mm thickness (0% risk of metastasis), “low risk” > 2 mm to 6 mm thickness

(4% risk of metastasis), and “high risk” > 6 mm thickness (16% risk of metastasis).

Immune suppression, poor differentiation/desmoplasia, and the ear as

tumor site are additional risk factors for metastasis, currently not evaluable.

N/A

Brinkman (2015)

B

Retrospective study

131 patients (155 SCCs)

Patients treated for cSCC with conventional surgical excision.

Median follow-up 81 months (from 65 patients)

Tumor characteristics, local recurrence, metastasis and patient survival (OS)

No significant correlation between tumordifferentiation grade and local recurrence (p=0.54)

Tumor differentiation grade was an independent prognostic factor for metastatic disease and overall survival

Metastatic-free survival at 5 years was significantly higher in well-differentiated tumors (70%) compared to moderately (51%) and poorly differentiated SCCs (26%; p=0.012); identical percentages were found for overall survival (p=0.005)

Patients with incomplete excision of the first tumor showed an increased relative risk of dying of SCC of 4.0 (95% CI 2.4-6.6; p<0.001) compared to excision with clear margins

NS

Univariate anaylsis was used in this study, therefore bias due to possible confounders.

Completed follow-up was only available for 65 patients.
 

Brougham (2012)

B

Prospective study

6164 patients (8997 cSCC)

Patients with primary cSCC

Median follow-up of 70 months

Patient demographics, max clinical diameter, anatomical sub-site, histological differentiation, perineural invasion and lymphovascular invasion

Primary endpoint was time to metastasis

Metastatic rate of cSCC was 1.9-2.6%

Multivariate analysis

Increased risk of metastasis:

- max clinical diameter (HR 1.41; 95% CI 1.25-1.60; p<0.001)

- perineural invasion (HR 5.29; p<0.0001)

- poor histological differentiation (HR 4.26; p<0.0001)

- location ear and retro-auricular area (HR 3.31; CI 1.17-9.33; p=0.0024)

- cheek (HR 3.18; CI 1.15-8.81; p=0.026)

- lip (HR 4.84; p=0.009)

NS

Chu (2014)

B

Retrospective chart study

269 cSCC in the head and neck

cSCC in the head& neck. Data including patient demographics,

tumor anatomic location and size, and histologic

subtype was documented for all tumors

N/A

Classification of tumours according to AJCC and NCCN. Proportion of high-risk cSCC according to AJCC criteria compared to proportion of high risk tumors by NCCN guidelines.

Few cSCCs are Stage 2 (14%) by AJCC staging criteria, while most (87%) are “high-risk” by the NCCN guidelines.

N/A

AJCC 7th edition- vs NCCN 2014

Griffiths (2002)

B

Prospective cohort

171 patients

Patients with invasive SCC, treated by conventional surgery

5 years

Clinical and histological factors SCC

157/171 patients were treated for invasive SCC. 64/157 (41%) died within 5 years of treatment from causes other than SCC

85/93 lived without recurrence or metastasis for at least 5 years after treatment. 8/93 died of their disease

Comparison groups alive/dead:

- tumour diameter and thickness were significantly greater in the patients who died (p=0.02; p=0.0057)

- no significant differences between the groups with regard to age, deep resection margin clearance, lateral epidermal resection margin clearance, lymphocyte response or degree of tumour differentiation

61 (41%)

Haisma (2016)Haisma (2016)

BB

Retrospective study Retrospective

336 patients with 545 tumors.336 patients met 545 HNcSCC’s

Complete clinical

and histopathologic information on 522 tumors obtained.

Patients with primary HNcSCCs.Patients with histologically proven primary HNcSCC

Median

follow-up period was 43 months The median

follow-up period was 43 months (range, 1-176 months).

Haisma (2016)

LN metastasis occurred in 55 patients (16.4%).

Moderate differentiation, poor differentiation,

tumor localization on the ear, tumor

diameter [50 mm, and tumor thickness [2 mm were identified as independent risk factors for LN metastasis in patients with HNcSCC.

Survival rates were significantly lower in patients with LN metastasis compared to patients without LN metastasis.

144 patients died  (118 due to other causes,

26 due to the disease).

Some tumours were diagnosed solely based on the review of

punch biopsy specimens (N = 79; 14.5%), which made this histopathologic information less reliable.27

Harris (2017)

B

Case series with chart review

212 patients

Patients with CSCCs of the head and neck treated

between January 1998 and June 2014.

The mean follow-up time was 35 months

Collected outcome data

included recurrence, date of recurrence, location of recurrence,

date of last follow-up, date of death, and cause of

death. Five-year estimates of disease-free

survival (DFS).

On Cox multivariate analysis, recurrent

disease, perineural invasion (PNI), and poorly differentiated

histology were independent predictors of recurrence.

PNI (HR = 2.62, P = .028)

poorly differentiated tumors (HR=2.62, p=0.028) and recurrent tumors ((HR = 2.21, p=0.041) were significantly associated with DFS.

N/A

Jambusaria-Pahlajani (2013)

B

Retrospective cohort study

256 tumours in 237 patients

Patients with primary high risk cSCC (single academic hospital) using 6 risk

strata: perineural or lymphovascular invasion, poorly differentiated

histologic characteristics, depth beyond subcutaneous

fat, diameter of at least 2 cm, location on the ear, or location

on the vermillion lip.

Median follow-up time: 44 months

Local recurrence, nodal metastasis, disease-specific death, all-cause death

21 local recurrences (8%), 25 nodal metastases (10%), 12 disease-specific deaths (5%) and 85 all-cause deaths (33%)

AJCC T stage

- T1: 112 tumors (54%)

- T2: 91 tumors (44%). 83% of nodal metastases and 92% of deaths from cSCC

- T3/T4: 4 tumors

4 risk factors (poor differentiation, perineural invasion, tumor thickness ≥2 cm, invasion beyond subcutaneous fat) were found to be statistically independent prognostic factors for at least 2 outcomes of interest in multivariate modeling

Alternative tumor staging system

T1: 0 factors

T2a: 1 factor

T2b: 2-3 factors

T3: 4 factors or bone invasion

Stages T2a and T2b significantly differed in incidences of all 4 endpoints. Stage T2b tumors comprised only 19% of the cohort, but accounted for 72% of nodal metastases and 83% of deaths from cSCC.

NS

HR with 95% CI’s are provided in a separate table in the article (table 2).

Krediet (2015)

B

Retrospective study

143 patients

Patients who underwent excision of cSCC between Jan 2005-Aug 2009

17 patients with SLNB

≥24 months

Occurrence of metastatic disease and/or local regional recurrence

Tumour thickness >4 mm and recurrent cSCC were strongly associated with metastatic disease

All metastases occurred <24 months of follow-up

SLNB showed a low sensitivity with regard to the development of metastases: 6/17 patients developed metastatic disease despite a negative SLNB

NS

Univariate analysis was used

Marrazzo (2015)

B/C

Retrospective study

82 patients

Patients that had undergone head and neck imaging for high-risk cSCC

NS

Clinical and pathologic features predictive of bony invasion, perineural invasion, or lymphadenopathy

29% (24/82) had positive findings on radiologic imaging

Correlations between clinical/pathological features and radiologic findings:

High-risk location

- bony invasion 17% (p=0.31)

- perineural invasion 4% (p=0.54)

- lymphadenopathy 15% (p=1.00)

High-risk pathology

- bony invasion 10% (p=0.72)

- perineural invasion 5% (p=0.45)

- lymphadenopathy 10% (p=0.72)

Immunocompromised

- bony invasion 10% (p=1.00)

- perineural invasion 0% (p=1.00)

- lymphadenopathy 40% (p=0.04)

Correlation of tumor size and high-risk feature count with radiologic findings:

Tumor size

- bony invasion CC 0.40 (p=0.0002)

- perineural invasion CC 0.03 (p=0.54)

- lymphadenopathy CC -0.09 (p=0.40)

High-risk feature

- bony invasion CC 0.14 (p=0.20)

- perineural invasion CC 0.13 (p=0.24)

- lymphadenopathy CC 0.12 (p=0.28)

-

Reason behind ordered imaging was not accurately determined in all cases. (i.e., imaging ordered for preoperative planning –vs-

a positive exam finding

Limitations of the study include its retrospective

design, small number of patients, and the performance

of multiple comparisons across a small sample size.

CT and MRI were computed

together in the evaluation of imaging findings. CT was the most

common imaging modality used

Mullen (2006)

B

Retrospective study

136 patients

Patients with invasive SCC of the trunk/extremities

NS

- Primary outcome: recurrence-free survival

- Secondary outcomes: disease specific survival and overall survival

Patterns of presentation:

Primary (n=5), locally recurrent (n=16), regional nodal (n=24) and distant (n=5) disease

Significant risk factors for recurrence or death:

Univariate analysis

- poorly differentiated carcinomas (HR 2.92; p=0.016)

- scar carcinomas (HR 3.12; p=0.008)

- tumor size >2 cm (HR=3.79; p=0.006)

- regional nodal disease (HR 5.77; p<0.0001)

Multivariate analysis

- regional nodal disease at presentation (HR 7.64; p<0.0001)

NS

Petter (1998)

C

Prospective study

184 patients

Patients with cSCC

Average 3 years

Histological parameters, carcinoma type, Breslow index, invasion level, growth form, grading and mitotic index

- progression in 17/184 (9%)

- recurrence in 8/184, metastasis in 4/184, recurrence+metastasis in 5/184

- total recurrence 13/184 (7%)

- total metastasis 9/184 (5%)

Histological findings

Typing:

- high-infiltration (desmoplastic) carcinomas showed more progression

- cumulative metastasis/recurrence-free survival at 3 years was 93% for tumours without desmoplastic type and 53% for patients presenting desmoplastic SCC

Microstaging:

- most tumours with progression were thicker than 3.5 mm

- thinnest metastasising carcinoma was 2.4 mm and thinnest recurring SCC showed a Breslow index of 1 mm

- metastatic spread and recurrence risk of carcinomas significantly increased (p=0.012) as the Breslow index rose

- cumulative metastasis/recurrence-free survival at 3 years was 98% for tumours of ≤3.5 mm and 84% for SCC >3.5 mm

- recurrence: Clark level IV or more

- metastasis: Clark level V

- as the invasion level increased (Clark level ≥V), the prognosis with respect to metastasis/recurrence significantly deteriorated (p=0.033)

- cumulative metastasis/recurrence-free survival at 3 years was 97% for tumours with a Clark level <V and 85% for SCC with a Clark level V

Clinical staging:

- T1 87% (n=167), T2 13% (n=22), T3 0%

- as tumour diameter increased, the probability of recurring/metastasising tumour growth also rose significantly (p=0.0001)

- at 3 years cumulative metastasis/recurrence-free survival was 95%

For SCC with a diameter ≤2 cm and 70% for carcinomas with a diameter >2 cm

NS

Methodology not clearly described in the article.

Quaedvlieg (2006)

B

Retrospective study

580 patients (915 SCC)

Metastatic skin and lip SCCs vs a matched group of non-metastasizing tumours

(1982-2002)

Mean follow-up 5.7 years

Tumour width, excision margins, histological subtype, Clark level, Breslow depth, tumour differentiation, inflammation, perineural and angio-invasive growth, ulceration and desmoplasia

Prevalence of metastasis for lip SCC 20.6% (13/63) and for skin SCC 6.5% (55/852)

Skin tumours (55 cases vs 55 controls):

Desmoplasia, Clark level, Breslow depth (>2.85 mm) and max diameter (>15 mm), angio-invasion, grading, perineural invasion, plasma cells and eosinophils were statistically significantly related to metastasis.

Multivariate analyses: 3 risk factors (max diameter of the tumour (in mm), having/not having desoplasia, reclassified trichotomous Clark index) and 1 protective factor (having/not having a lymphocytic infiltrate)

Lip tumours (13 cases vs 50 controls):

Breslow depth (>4.8 mm), plasma cells and grading were statistically significantly related to metastasis

Of the tumours with Breslow thickness >4.8 mm 53% metastasized vs 0% of the SCCs <4.8 mm

Breslow thickness was a statistically significant prognostic factor for metastasis (OR 3.71; p<0.001)

Multivariate analysis: 1 risk factor (having/not having infiltrate of plasma cells)

NS

Possible publication bias due to seemingly random tresholds.

Roozeboom (2012)

B

Retrospective study

224 patients

Patients with histopatholologically confirmed cSCC at any body site.

(1 Jan 2005-31 Dec 2007). One tumour per patient was analysed.

Median follow-up period 43 months

1-,2-and-4 year local recurrence-free survival, Local recurrence, metastasis and metastasis-free survival.

1-, 2- and 4-year cumulative probabilities of local recurrence-free survival were 98.0% (95% CI 94.8– 99.3%), 96.9% (95% CI 93.2–98.6%) and 94.7% (95% CI 89.9–97.2%), respectively

Cumulative probabilities of metastasis-free survival were 98.1% (95% CI 95.1–99.3%), 97.0% (95% CI 93.4–98.6%) and 95.9%

(95% CI 91.1–98.1%) at 1, 2 and 4 years, respectively

Univariate survival analyses:

- Local recurrence:

Significant predictors were tumour diameter (HR 1.1 (1.0-1.1), p=0.015 )and tumour thickness: (HR 1.3 (1.1-1.5), p<0.0001 )

- Metastasis:

Significant predictors were invasion of deeper structures (HR 2.8 (4.6-93.7) p<0.0001), location on the ear (HR 21.3 (2.5-182.2), p=0.005), poor differentiation (HR 15.7 (3.5-70.3), p<0.0001), tumour diameter (HR 1.1 (1.0-1.1), p=0.001)and tumour thickness (HR 1.2 (1.1-1.4) , p=0.010)

Multivariate survival analysis:

Every mm increase in tumour diameter and thickness were independent predictors for local recurrence and metastasis

NS

Interobserver agreement was poor

for part of the studied histopathological characteristics.

Schmults (2013)

B

Retrospective study

985 patients (1832 tumors)

Patients with cSCC

Median follow-up 50 months

Subhazard ratios for local recurrence, nodal metastasis, disease-specific death, and all-cause death adjusted for presence of known prognostic risk factors

- Local recurrence in 45 patients (4.6%)

- Nodal metastasis in 36 patients (3.7%)

- 21 died of cSCC (2.1%)

Multivariate analysis

Independent predictors for nodal metastasis and disease-specific death were:

- tumor diameter of 2 cm (subhazard ratios 7.0; 95% CI 2.2-21.6 and 15.9; 4.8-52.3)

- poor differentiation (6.1; 2.5-14.9 and 6.7; 2.7-16.5)

- invasion beyond fat (9.3; 2.8-31.1 and 13.0; 4.3-40.0)

- ear or temple location (3.8; 1.1-13.4 and 5.9; 1.3-26.7)

Disease-specific death:

- perineural invasion (3.6; 1.1-12.0)

- anogenital location (few cases)

Overall death was associated with poor differentiation (1.3; 1.1-1.6) and invasion beyond fat (1.7; 1.1-2.8)

-

Underpowered to assess all risk factors with prognostic significance.

Tan

(2007)

B

Prospective study

517 SCC

Patients with SCC

NS

Patient age, sex, lesion size, margin of excision, recurrence,

previous excision, site, anesthetic choice, and repair method

Overall incomplete excision rate was 6.3%

Risk factors for incomplete resection:

- Lesions on the ear (p<0.003)

- re-excisions (p<0.001)

- invasive lesions (p<0.001)

NS

Factors that may be confounding

included age, size of lesions, method of repair, and

experience of the surgeon

Thompson
(2016)

A1

Systematic review

36 studies (17248 patients with 23421 cSCC)

Studies of at least 10 patients, comparative data for at least 1 cSCC risk factor and an outcome of interest

NS

Recurrence, metastasis and disease-specific death

Significant risk factors for recurrence:

- Breslow thickness >2 mm (RR 9.64; 95% CI 1.30-71.52)

- invasion beyond subcutaneous fat (RR 7.61; 95% CI 4.17-13.88)

- Breslow thickness >6 mm (RR 7.13; 95% CI 3.04-16.72)

- perineural invasion (RR 4.30; 95% CI 2.80-6.60)

- diameter >20 mm (RR 3.22; 95% CI 1.91-5.45)

- location on the temple (RR 3.20; 95% CI 1.12-9.15)

- poor differentiation (RR 2.66; 95% CI 1.72-4.14)

Significant risk factors for metastasis:

- invasion beyond subcutaneous fat (RR 11.21; 95% CI 3.59-34.97)

- Breslow thickness >2mm (RR 10.76; 95% CI 2.55-45.31)

- Breslow thickness >6 mm (RR 6.93; 95% CI 4.02-11.94)

- diameter >20 mm (RR 6.15; 95% CI 3.56-10.65)

- poor differentiation (RR 4.98; 95% CI 3.30-7.49)

- perineural invasion (RR 2.95; 95% CI 2.31-3.75)

- Immunosuppression (RR 1.59; 95% CI 1.07-2.37)

- location on the temple (RR 2.82; 95% CI 1.72-4.63)

- location on the ear (RR 2.33; 95% CI 1.67-3.23)

- location on the lip (RR 2.28; 95% CI 1.54-3.37)

Significant risk factors for disease-specific death:

- diameter >20 mm (RR 19.10; 95% CI 5.80-62.95)

- poor differentiation (RR 5.65; 95% CI 1.76-18.20)

- location on the ear (RR 4.67; 95% CI 1.28-17.12)

- location on the lip (RR 4.55; 95% CI 1.41-14.69)

- invasion beyond subcutaneous fat (RR 4.49; 95% CI 2.05-9.82)

- perineural invasion (RR 4.06; 95% CI 3.10-5.32)

NS