9. Follow-up and prevention – Actinic keratosis and squamous cell carcinoma of the skin

Efird et al 2002

To determine the risk of subsequent cancer following squamous cell skin cancer

Retrospective review; n=822

Individuals with primary squamous cell skin cancer (SCSC) and their comparison subjects matched for age, sex, race, residence area, and length of membership. Patients were included in the study if they had no prior history of cancer and received at least one multiphasic health checkup and questionnaire (MHC).

Subsequent cancer risk after SCSC diagnosis

Patients were followed for subsequent invasive cancer up to 24 years, with a mean follow-up time of 7.8 years. SCSC patients had a significantly greater risk [adjusted for body mass index (BMI) and education] for subsequent cancer overall (excluding non-melanoma skin cancer) [risk ratio (RR) =1.4, 95% confidence interval (CI) =1.2–1.6], and for basal cell skin cancer (RR =13.8, 95% CI = 8.8–21.9), digestive (RR =1.6, 95% CI =1.1–2.4), and genitourinary cancers (RR =1.5, 95% CI =1.0–2.0). An increased, but not statistically significant, adjusted risk (RR >=1.4) was also observed for lip, oral cavity, and pharynx cancer (RR =3.9, 95% CI = 0.6–25.0); non-cutaneous squamous cell cancer (RR = 1.9, 95% CI = 0.9–4.4); and respiratory and intrathoracic cancer (RR = 1.4, 95% CI = 0.8–2.6). The addition of alcohol consumption, combined occupational exposure, marital status, and smoking history to the multivariate model did not materially change any significant positive associations with SCSC.

The results suggest that patients diagnosed with SCSC may be at an increased risk of subsequent cancer at many sites, although several estimated risk estimates were within the limits of chance given no true association.

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Griffiths et al 2002

To establish the 5-year survival and outcome for patients after conventional surgery, related to tumour characteristics and specific tumour measurements

Retrospective cohort study; n=171

Patients with primary invasive squamous cell carcinoma of the skin, followed for a minimum of 5 years after treatment with conventional excisional surgery, in one center, between 1990 and 1995.

Patient outcomes - either alive without recurrence or metastasis at 5 years, dead of disease within 5 years or dead of other causes within 5 years.

Of these 171 patients, 157 were confirmed as having been treated for invasive squamous cell carcinoma, of whom 64 (41%) died within 5 years of treatment from causes other than squamous cell carcinoma, and were therefore defined as indeterminate. The remaining 93 patients were determinate patients; 85 lived without recurrence or metastasis for at least 5 years after treatment, and eight died of their disease. Comparing the groups who were alive or had died of disease at 5-year follow-up, the tumour diameter and tumour thickness were significantly greater in the eight patients who died (P = 0.02 and P =0.0057, respectively) but there were no  significant differences between the two groups concerning age, deep resection margin clearance, lateral epidermal resection margin clearance, lymphocyte response or degree of tumour differentiation.

There is no evidence that the prognosis is superior after either conventional surgery or Mohs' therapy, when series are compared for tumour thickness. Long-term follow-up and tumor-thickness measurements are required in all series after all treatments for meaningful comparisons to be made.

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Harris et al 2017

To evaluate which factors are predictive of recurrence and nodal spread and survival in patients with cHNSCC treated surgically

Retrospective review; n=212

Patients with CSCCs of the head and neck treated between January 1998 and June 2014. All patients undergoing primary surgery, with or without adjuvant therapy, with curative intent for CSCC were included. Patients were excluded if they had distant metastases at presentation, were treated with palliative intent, and had <3 months of follow-up.

5-years DFS

DSS

OS

Associations of patient and tumor characteristics with recurrence and survival

Factors independently associated with the presence of nodal metastasis at presentation

A total of 212 patients met inclusion criteria, with a mean age of 70.4 years; 87.3% were men. Mean tumor diameter was 3.65 cm, with an average depth of invasion of 1.38 cm. The mean follow-up time was 35 months (median, 21.5), and over that period 67 recurrences were recorded, 49 of which were local. The 5-year Kaplan-Meier estimate of DFS for the cohort was 53.2%. On Cox multivariate analysis, recurrent disease, perineural invasion (PNI), and poorly differentiated histology were independent predictors of recurrence. On multinomial logistic regression, patients with primary tumors on the ear, cheek, temple, or lip, as well as those with PNI, were more likely to present with nodal metastasis.

Analysis of OS and DSS was limited given incomplete cause of death data and the advanced age of the patient cohort.

For advanced CSCCs of the head and neck, patients with recurrent disease, PNI, and poorly differentiated tumors are at the highest risk for local recurrence. Patients with tumors or the ear, cheek, temple, or lip, as well as those with PNI, are at increased risk of harboring nodal disease.

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Kim et al 2018

Guidelines of care for the management of cutaneous squamous cell carcinoma

An expert workgroup was convened to determine the audience and scope of the guideline, and to identify important clinical questions in the biopsy, staging, treatment, and follow-up of cSCC.

An evidence-based approach was used and available evidence was obtained by using a systematic search and review of published studies from PubMed and the Cochrane Library databases from January 1960 through April 2015 for all identified clinical questions. A secondary search was subsequently undertaken to identify and review published studies from April 2015 to August 2016 to provide the most current information

After the diagnosis of a first SCC, screening for new keratinocyte cancers (BCC or cSCC) and for melanoma should be performed on at least an annual basis.

Patients with a history of cSCC should be counseled on skin self-examination and sun protection.

Topical and oral retinoids (eg, tretinoin, retinol, acitretin, and isotretinoin) should not be prescribed to reduce the incidence of keratinocyte cancers in those with a history of cSCC, unless they are SOTRs. In the situation of SOTRs, only acitretin may be beneficial.

Dietary supplementation of selenium and b-carotene is not recommended to reduce the incidence of future keratinocyte cancers in those with a history of cSCC.

There is insufficient evidence to make a recommendation on the use of oral nicotinamide, DFMO, or celecoxib in the chemoprevention of cSCC.

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Levine et al 2015

To compare outcomes in patients with 1 vs multiple cutaneous squamous cell carcinomas (CSCCs).

Retrospective, single-center cohort; n=985

Patients with dermally invasive (non–in situ) primary CSCC diagnosed from January 1, 2000, through December 31, 2009, from a tertiary center

Tumor stage (Brigham and Women’s Hospital tumor stage) and outcomes (local recurrence [LR], nodal metastases [NM], and death due to CSCC)

Outcomes were compared between patients with 1 vs more than 1 CSCC via multivariable competing-risk regression adjusted for other significant cofactors.

Of 985 patients with CSCC, 727 had 1 CSCC, 239 had 2 to 9 CSCCs, and 19 had 10 or more CSCCs. Most patients with 10 or more CSCCs were immunosuppressed (15 of 19 [78.9%]). The median follow-up time was 50 months (range, 2-142 months). Patients with more than 1 CSCC had a higher risk of LR (subhazard ratio for 2-9 CSCCs, 1.8; 95%CI, 1.1-4.3; and for ≥10 CSCCs, 3.8; 95%CI, 1.4 - 10.0) and NM (subhazard ratio for 2-9 CSCCs, 3.0; 95% CI, 1.4-6.5; and for ≥ 10 CSCCs, 4.2; 95%CI, 1.4-10.4) compared with patients with 1 CSCC, adjusted for Brigham and Women’s Hospital tumor stage. The 10-year cumulative incidence of LR and NM was higher in patients with 2 to 9 CSCCs and markedly higher in those with 10 or more CSCCs compared with patients who had 1 CSCC (10-year cumulative incidence for 1 CSCC: LR, 3.0%; 95%CI, 2.0%-4.5%; and NM, 2.3%; 95%CI, 1.5%-3.8%; for 2-9 CSCCs: LR, 6.7%; 95%CI, 4.2%-10.6%; and NM, 5.9%; 95%CI, 3.5%-9.6%; and for ≥10 CSCCs: LR, 36.8%; 95%CI, 19.2%-59.0%; and NM, 26.3%; 95%CI, 11.8%-48.8%).

Patients with multiple CSCCs warrant frequent follow-up because they have an elevated risk of LR and NM. In particular, patients with 10 or more CSCCs have markedly elevated risks of recurrence and metastasis.

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Mahajan et al 2019

To analyze the diagnostic performance of 18F-FDG-PET/CT in staging patients with newly diagnosed cSCC.

Retrospective analysis; n=23

Patients with biopsy-proven cSCC who underwent 18F-FDG scan at diagnosis in one institution from 2000 to 2016.

Sensitivity and specificity of 18F-FDG-PET/CT

Twenty-three cSCC patients who underwent 18F-FDG-PET/CT at diagnosis were evaluated. Primary sites were in head/neck (n=21), chest (n=1), and foot (n=1). All patients had 18F-FDG-positive scans with a total of 51 18F-FDG-positive lesions. All primary lesions (n=24) were 18F-FDG-positive (SUV: 2.3–22.8; mean 10.2), and additional 27 18F-FDG-positive lesions, including 21 nodes, four cutaneous, one osseous and one lung lesion, were noted in 13 patients. Mean size of 18F-FDG-positive nodes was 0.9 cm (range: 0.4–2.5 cm), predominantly clinically impalpable. Pathology was available for 40/51 lesions; 31 sites positive for malignancy. SUV (mean ± SD) was 9.2 ± 6.2 for malignant and 2.7 ± 1.2 for benign lesions. Sensitivity, positive predictive value, and accuracy of 18F-FDG-PET/CT scan were 100, 77.5, and 77.5%, respectively. Overall, staging 18F-FDG detected nine prior unknown lesions in five patients that were proven metastatic disease by histopathology or follow-up; 18F-FDG-PET/CT modified management in 5/23 (21.7%) patients

18F-FDG-PET/CT has high sensitivity in the detection of cSCC lesions, including small cutaneous and nodal disease, and has a potential role in initial staging and management.

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McLaughlin et al 2017

To determine the rate of regional lymph node involvement in a large cohort of solid organ transplant patients with cutaneous head and neck squamous cell carcinoma (cHNSCC)

Retrospective chart review; n= 30 solid organ transplant patients; 383 cHNSCC ressections

All solid organ transplant recipients who underwent surgery between 2005 and 2015 for a cHNSCC at the Hospital of the University of Pennsylvania Department of Dermatology and/or Otorhinolaryngology

Rate of regional lymph node involvement

Time from the first diagnosis to regional lymphatic disease

The average age of the patient was 63. Seven patients (5%) developed regional lymph node metastases (3 parotid, 4 cervical lymph nodes). The mean time from primary tumor resection to diagnosis of regional lymphatic disease was 6.7months. Six of these patients underwent definitive surgical resection followed by adjuvant radiation; one patient underwent definitive chemoradiation. 6 of the 7 patients died of disease progression with a mean survival of 15months. The average follow-up time was 3years (minimum 6months).

Solid organ transplant recipients with cutaneous squamous cell carcinoma of the head and neck develop regional lymph node metastasis at a rate of 5%. Regional lymph node metastasis in this population has a poor prognosis and requires aggressive management and surveillance.

This is the largest study to date of cSCC in solid organ transplant patients. In addition, all of these lesions were limited to the head and neck. Despite the low rate of regional lymph node involvement demonstrated in these patients, their extremely poor prognosis makes managing an N0 neck in an immunocompromised patient a difficult clinical dilemma.

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Picard et al 2017

To search for somatic mutations of the HRAS, KRAS, NRAS, BRAF and EGFR genes in patients with advanced cSCC treated with cetuximab; and to investigate the efficacy and tolerance of cetuximab according to these mutations

Multicenter retrospective study; n=31

Patients with confirmed advanced cSCC treated in two medical oncology departments in France between January 2008 and December 2014

Incidence of somatic mutations of the RAS, BRAF and EGFR genes and association with cetuximab efficacy with these mutations – Fisher test

Disease control rate at week 6

PFS

OS

Safety

31 samples of cSCC from 31 patients were analyzed. Only 2 RAS muated samples (6.5%) were identified. The first harbored an NRAS point mutation (c.35G>A) in codon 12, resulting in a p.G12D substitution. The second sample presented an HRAS point mutation (c.38G>T) in codon 13, resulting in p.G13V  substitution. No mutation of KRAS, BRAF and EGFR genes at the investigated loci was found. Two patients with NRAS and HRAS mutations showed a partial and complete response to cetuximab, respectively. The mean duration of follow-up was 19 months. At week 6, the disease control rate was 67.8%. The median OS was 13 months and the median PFS was 9 months. All patients could continue cetuximab treatment without dose reduction.

Even in elderly patients (median age 86 years; range 48-96 years), cetuximab was efficacious and well-tolerated. This suggests that cetuximab is certainly warranted in the treatment of cSCC. However, it is also important to identify tumor-specific mutations that may determine response to treatment and prognosis for the disease. We have identified here that the incidence of RAS, BRAF and EGFR mutations is low in cSCC.

The authors concluded that the incidence of RAS, BRAF and EGFR mutations is very low in cSCC. The search for mutations appears unnecessary before initiating a cetuximab treatment for advanced cSCC, but ultimately mutational data are needed to better define the genetic landscape of this disease.

Dr. Frederic Peyrade is a Merck board Member.

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Rose et al 2017

To review the outcomes for sporadic primary cSCC in one department, to identify a sub-group of “low-risk” cutaneous squamous cell carcinoma (cSCC) patients suitable for discharge to primary care without extended out-patient follow-up.

Retrospective review; n=320 patients; n= 336 primary invasive cSCC

Patients with primary invasive cSCC excised within a single plastic surgery department between 2011 and 2015

To identify a sub-group of “low-risk” cutaneous squamous cell carcinoma (cSCC) patients suitable for discharge to primary care without extended out-patient follow-up.

Tumours were staged by American Joint Committee on Cancer (AJCC e 7th Edition) and Brigham and Women’s Hospital (BWH) classification systems. Tumours were then stratified into 4 risk groups: Group 1 (High-1), Group 2 (High-2), Group 3 (Intermediate) and Group 4 (Low).

Follow-up practices for this “low-risk” Group 4 (Low) were then scrutinized using clinical-portal “e-health” records. The financial cost of “low-risk” disease to out-patient services, both locally and nationally, was estimated using publically available specialty-specific health service cost data.

Group 4 (Low) patients consisted of 94 tumours (27.9%). There were no episodes of locoregional recurrence or SCC-related death in this group. At the time of analysis, 59 (67%) patients remained under active follow-up. Only 25 (26.6%) were discharged to primary care. Importantly, 18 (30.5%) Group 4 (Low) patients died of causes unrelated to their cSCC during their follow-up. 32 (34%) Group 4 (Low) patients developed further lesions. Most common were actinic keratosis (13.8%) and basal cell carcinoma (11.7%), only 6 (6.4%) developed a further cSCC.

During the follow-up period Group 4 (Low) patients were reviewed in outpatient clinics on 536 occasions (a mean of 5.8 visits per patient; range 0e14). Presuming each out-patient appointment was allocated a standard 10-min review consultation, this amounts to 89.3 h clinic time (almost 12x3-h out-patient clinics/year). Using a conservative estimate of £120 per out-patient appointment, this represents a total departmental cost of £64,320 over the study period (around £25,000/year). 3130 cSCC were registered in Scotland in 2014. If we extrapolated our data and follow-up practices nationwide, this would equate to around 873 “low-risk” cSCC patients treated, subsequently filling 5000 out-patient appointments and around 833 h of clinic time (almost 111 x 3-h out-patient clinics/year), to a cost of £597’0000 (around £240,000/year).

The primary aim of out-patient follow-up for cSCC is to screen for loco-regional recurrence. In conclusion, this data suggests it is unnecessary and costly to commit an elderly co-morbid population with adequately treated “low-risk” disease to specialist out-patient follow-up.

The authors recommend a realistic approach to the follow-up of immunocompetent patients with “low-risk” tumours, single out-patient visit to review histopathology, council on sun protection and self-examination and then discharge to primary care.

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Ruiz et al 2018

To review utilization of radiologic imaging of high-stage CSCCs to evaluate whether imaging impacted management and outcomes.

Retrospective analysis; n=103

all patients with a diagnosis of cutaneous squamous cell carcinoma from January 1, 2000 through May 30, 2013

Disease-related outcomes (DRO: local recurrence, nodal metastasis, death from disease)

108 high-stage CSCCs in 98 patients were included. Imaging (mostly computed tomography, 79%) was utilized in 45 (46%) patients and management was altered in 16 (33%) patients who underwent imaging. Patients that received no imaging were at higher risk of developing nodal metastases (nonimaging, 30%; imaging, 13%; P = .041) and any DRO (nonimaging, 42%; imaging, 20%; P = .028) compared to the imaging group. Imaging was associated with a lower risk for DRO (subhazard ratio, 0.5; 95% CI 0.2-0.9; P = .046) adjusted for BWH T stage, sex, and location.

Radiologic imaging of high-stage CSCC may influence management and appears to positively impact outcomes. Further prospective studies are needed to establish which patients benefit from imaging.

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Supriya et al 2014

To evaluate the impact of whole-body positron emission tomography in comparison to staging by conventional methods alone in the management of patients with head and neck cutaneous squamous cell cancer (cSCC) with confirmed regional nodal metastasis.

Retrospective case cohort study; n=31

Patients with head and neck cSCC and regional nodal metastasis  diagnosed from 1 January 2009 to 31 December 2010

Impact of 18F-FDG PET–CT on patient management

The original treatment plan based on conventional cross-sectional imaging and clinical examination were compared to the final treatment plan after additional PET staging to evaluate the impact of 18F-FDG PET–CT on patient management.

Addition of 18F-FDG PET–CT did not change the management in 24/31 (77%) of patients. In four cases the 18F-FDG PET–CT failed to pick up a biopsy-proven metastatic disease. Two patients who had reduced extent of surgery have shown no features of regional failure after one year of follow-up.

Overall the management in majority of head and neck cSCC patients with regional metastasis does not change by the addition of 18F-FDG PET–CT over conventional imaging.

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Stratigos et al 2020

To make recommendations on treatment, supportive care, education and follow-up of patients with invasive cutaneous squamous cell carcinoma (cSCC)

Recommendations were based on evidence-based literature review, guidelines and expert consensus. Treatment recommendations are presented for common primary cSCC (low risk, high risk), locally advanced cSCC, regional metastatic cSCC (operable or inoperable) and distant metastatic cSCC.

EDF–EADO–EORTC guideline

Follow-up

The frequency of follow-up visits and investigations for subsequent new cSCC depend on underlying risk characteristics.

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Wassberg et al 1999

To report second primary cancers in patients with skin squamous cell carcinoma (SCC)

A population-based study; n=25947

Patients diagnosed with SCC in Sweden between 1958 and 1992.

Second primary cancers incidence

In total, 5,706 patients developed a second primary cancer at any site, compared with an expected number of 2,651 [standardized incidence ratio (SIR) = 2.15; 95% confidence interval (CI) = 2.10–2.21]. Men below 60 years of age at diagnosis of SCC had higher SIR (2.5; CI = 2.2–2.8) with the highest risk during the first year of follow-up (SIR = 9.2; CI = 6.9–12.2). If the second primary SCC was excluded, the SIR was reduced to 1.30 (CI = 1.25–1.34); the relationships by sex, age and time since diagnosis remained similar. For skin cancer, the SIR for second SCC was markedly elevated (SIR = 15.6) and the risk of malignant melanoma was elevated 3-fold. Significantly increased risks were found for most second cancers in squamous cell epithelium: lip (SIR = 5.2), respiratory organs (SIR = 1.7), esophagus (SIR = 1.5), cervix uteri (SIR = 2.2), and vulva including vagina (SIR = 2.3). There was a generally increased risk of almost 2-fold for second cancer in hematopoietic or lymphoproliferative tissues. Slightly increased rates (SIR = 1.0–1.5) were seen for second tumors in digestive tissues. Finally, a high SIR (SIR = 5.5) was observed for second primary cancer in salivary glands.

Patients with SCC are at increased risk To develop new primary cancer, especially in skin, squamous cell epithelial and tobacco-related tissues. Common risk factors among the tumor types might explain our findings, however, an intrinsic susceptibility among SCC patients to develop cancer is also possible.

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Yoong et al 2009

To establish appropriate follow-up times and to determine the long-term risk of subsequent non-melanoma skin

cancers and melanoma.

Retrospective study; n=40

Patients who had a primary invasive cutaneous SCC excised during 1996 were retrospectively identified from the databases of a dermatologist in private practice in south-east Queensland.

Lymph node status

Patient’s immunocompetency

Presence of local recurrence, subsequent SCC, BCC and melanomas

The median follow-up time was 7.5 years. In the 10 years, there was one local recurrence of a well-differentiated SCC, which was detected at the 6 months follow up and following re-excision there was no further recurrence at the site and no metastases detected. In the entire audited group, 65% had a subsequent SCC detected. Half the patients developed a second SCC within 5 years of the index cutaneous invasive SCC, and 10% had a second SCC detected after only 5 years of follow-up. In the subgroup of patients followed up 5 years and more, 82.1% had a subsequent invasive SCC, 32.1% had invasive SCC detected within 12 months of the incident invasive SCC (this particular group had further invasive SCC detected in the audit period), 75% had invasive SCC detected in the 5–10 year follow up, and 14.3% had SCC detected only in the 5–10 year follow-up period. Of the entire audited group, 72.5% had a BCC within 5 years, and 82.5% at 10 years. The total number of BCC detected far exceeded that of invasive SCC, and 52.5% had BCC detected within 12 months of incident invasive SCC. One in eight patients had a subsequent melanoma detected.

These data which extended to 10 years, showed a significant rise in detection of further SCC as well as BCC in the period beyond 5 years. Of concern is the 10% who had their second SCC detected only in the 5–10 year follow-up period. The authors believe that these figures from our study would justify at least a 10-year follow up and we would strongly advise lifetime review.

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