Seminar

Non-melanoma skin cancer

Vishal Madan, John T Lear, Rolf-Markus Szeimies

The rising incidence and morbidity of non-melanoma skin cancers has generated great interest in unravelling of their Lancet 2010; 375: 673–85
pathogenesis and in the search for new non-invasive treatments. Whereas the role of cumulative sun exposure in Dermatology Centre, Salford
pathogenesis of squamous-cell carcinoma seems clear, the relation between sun-exposure patterns and subtypes of Royal Hospital NHS Foundation
Trust, Salford, UK
basal-cell carcinoma remains undetermined. Several complex genotypic, phenotypic, and environmental factors (V Madan MRCP, J T Lear FRCP);
contribute to pathogenesis of non-melanoma skin cancers. Unlike basal-cell carcinoma, squamous-cell carcinomas and Klinik und Poliklinik für
can arise from precursor lesions. Diagnosis of non-melanoma skin cancer is made clinically and confirmed by Dermatologie,
histological testing. Prognosis depends on lesion and host characteristics, which also dictate choice of treatment. Universitätsklinikum
Regensburg, Regensburg,
Prevention strategies aim at reduction of sun exposure, but are of unproven benefit, especially for basal-cell carcinoma. Germany (R-M Szeimies MD)
Surgical excision with predetermined margins is the mainstay of treatment for squamous-cell carcinoma and for Correspondence to:
most basal-cell carcinomas. Of the new non-invasive treatments, only photodynamic therapy and topical imiquimod Dr John T Lear, Dermatology
have become established treatments for specific subtypes of basal-cell carcinoma, and the search for more effective Centre, Salford Royal Hospital
and tissue-salvaging therapies continues. NHS Foundation Trust, Salford,
Lancs M6 8HD, UK
john.lear@srft.nhs.uk
Introduction in total number of patients was also noted.2 Rising
The term non-melanoma skin cancers (or keratinocyte incidence of non-melanoma skin cancer might partly be
carcinomas) encompasses cutaneous lymphomas, due to increased patient and physician awareness of the
adnexal tumours, Merkel-cell carcinomas, and other rare disease, in addition to improved coding.
primary cutaneous neoplasms, but is mainly used to The age shift in the population has resulted in an overall
define basal-cell carcinomas and squamous-cell increase in total number of skin cancers, since incidence
carcinomas. Grouping of these two carcinomas under a of non-melanoma skin cancer increases with age. Indeed,
common umbrella term poses challenges, because clear 80% of cases occur in people aged 60 years and older.10 By
differences exist in their aetiopathogenesis, clinical 2030, the number of cases presenting to dermatologists
course, and management strategies. Non-melanoma skin could increase by an estimated 50%.10 Incidence is higher
cancers are the most common human cancers, and in men than in women. Table 1 shows international trends
despite growing public awareness of the harmful effects in incidence of non-melanoma skin cancer.2,9,11–15
of sun exposure, incidence continues to rise.1,2 A 3–8% Risk of development of non-melanoma skin cancer
yearly increase in incidence of non-melanoma skin depends on genotypic, phenotypic, and environmental
cancer has been reported since 1960 worldwide.3,4 factors. Risk is greatest in residents of high ambient solar
Incidence of basal-cell carcinoma alone is increasing by irradiance who have markers of ultraviolet (UV)
10% per year worldwide, suggesting that prevalence of susceptibility, such as light skin, eye, and hair colour, or
this tumour will soon equal that of all other cancers an inability to tan, and those with benign sun-related skin
combined.5 Furthermore, an estimated 40–50% of disorders—eg, actinic keratoses and solar lentigines.16
patients with a primary carcinoma will develop at least The finding that non-melanoma skin cancer occurs
one or more further basal-cell carcinomas within 5 years. mainly on sun-exposed body sites and that its frequency
The estimated incidence of non-melanoma skin cancer can be reduced by sun protection provides indirect but
in the USA is more than 1 000 000 cases per year, of which crucial evidence for the role of ambient solar radiation.17
roughly 20–30% are of squamous-cell carcinoma.6 The geographic variation in incidence of non-
melanoma skin cancer is associated with ambient sun
Epidemiology irradiance, providing further evidence for the relation
Unfortunately, because of variation between registries in between this disease and sun exposure. Incidence within
data capture, recording, and processing for skin-cancer countries is associated with increasing proximity to the
registration, accurate figures for incidence of non-
melanoma skin cancer in the UK are difficult to obtain.7
More than 76 000 new cases of non-melanoma skin cancer Search strategy and selection criteria
were registered in the UK in 2005, but the actual incidence We searched PubMed, Medline, Embase, and the Cochrane
is estimated to be at least 100 000 cases per year.8 Results Library (from January, 1985, to March, 2009) using the terms
of a Welsh study9 showed that the crude incidence of non- “non melanoma skin cancer melanoma”, “basal cell
melanoma skin cancer increased from 173·5 to 265·4 per carcinoma”, and “squamous cell carcinoma”, with relevant
100 000 population yearly between 1988 and 1998. In subheadings. Reference lists of identified reports were
Northern Ireland, in the 10 years after 1993, incidence of searched for additional relevant articles. Several review
melanoma and non-melanoma skin cancer increased by articles providing comprehensive overviews of topics outside
62% in the overall number of skin-cancer samples the scope of this Seminar were included as references.
processed by local pathology laboratories. A 20% increase

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locations in the USA, suggesting a strong association

Basal-cell carcinoma Squamous-cell carcinoma
between UV radiation and development of non-
Age-standardised yearly Estimated yearly Age-standardised yearly Estimated yearly melanoma skin cancer.
incidence (per 100 000 change (%) incidence (per 100 000 change (%)
population) population) Although UV radiation is the most important risk
factor for pathogenesis of both basal-cell and squamous-
Northern Ireland (2007)2
cell carcinoma, the effect on risk of squamous-cell
Men 94·0 (world) 1·5% (world) 46·0 (world) 0·6% (world)
carcinoma is greatest.20 Cumulative lifetime sun exposure
Women 72·0 (world) –0·6% (world) 23·0 (world) –0·2% (world)
has a strong dose-response association with squamous-
Germany (2003)11
cell carcinoma, whereas for basal-cell carcinoma,
Men 53·6 (world); 80·8 (Europe) ·· 11·2 (world); 18·2 (Europe) ··
intermittent sun exposure and exposure during
Women 44·0 (world); 63·3 (Europe) ·· 5·3 (world); 8·3 (Europe) ··
childhood might be more important.21,22 The relation
Wales (2000)9
between sun exposure and development of basal-cell
Men 127·9 (world) ·· 25·2 (world) ·· carcinoma remains unclear, and epidemiological studies
Women 104·8 (world) ·· 8·6 (world) ·· suggest that the quantitative effect could be quite small.
Netherlands (2004)12 Additionally, various sun-exposure patterns might cause
Men 93·0 (Europe) 2·4% (Europe) ·· ·· specific histotypes at different sites.23 Morphological
Women 82·0 (Europe) 3·9% (Europe) ·· subtypes of basal-cell carcinoma might have distinct
Australia (2006)13 gene expression profiles, which partly account for their
Men 1041·0 (world); ·· 499·0 (world); ·· complex behaviour.24
1541·0 (Australia) 772·0 (Australia)
Women 745·0 (world); ·· 291·0 (world) ··
1070·0 (Australia) 442·0 (Australia)
Pathogenesis
UVB radiation causes direct damage to DNA and RNA by
Scotland (2007)14
inducing covalent bond formation between adjacent
Men 60·6 (world) 1·4% (world) 24·0 (world) 2·1% (world)
pyrimidines, leading to generation of mutagenic
Women 47·4 (world ) 1·9% (world) 9·4 (world) 3·5% (world)
photoproducts such as cyclopyrimidine dimers (TT) and
Canada (2007)15
pyrimidine-pyrimidine (6-4) adducts.25 UVA is less
Men 87·0 (world) ·· 34·0 (world) ··
mutagenic than is UVB, and causes indirect DNA damage
Women 68·0 (world) ·· 16·0 (world) ··
via a photo-oxidative-stress-mediated mechanism, result-
Table 1: International trends in incidence of non-melanoma skin cancers ing in formation of reactive oxygen species, which interact
with lipids, proteins, and DNA to generate intermediates
that combine with DNA to form adducts.26 Several complex
Type of non-melanoma DNA repair systems are needed to prevent the harmful
skin cancer
effects of these premutagenic adducts.27
Solar UV radiation16,17,20–22 BCC, SCC Reports in patients with a rare cell-mediated immunity
Human papillomavirus28–33 SCC, BCC disorder, epidermodysplasia verruciformis, of high rates
Iatrogenic immunosuppression34–37 SCC, BCC of malignant transformation of atypical warts infected
HIV/AIDS and non-Hodgkin lymphoma38–39 BCC, SCC with β human papillomaviruses (HPV) provided initial
PUVA therapy40,41 SCC, BCC clues about the association between HPV and non-
Photosensitising drugs (eg, fluoroquinolone SCC, BCC melanoma skin cancer.28 Further evidence arose from
antibiotics)42 estimates that up to 90% of non-melanoma skin cancers
UVB radiation43 BCC in immunocompromised individuals and up to 50% in
Ionising radiation44 BCC immunocompetent individuals contain DNA from
Occupational factors45,46 BCC, SCC cutaneous or β HPV types.28,29 Unlike for cervical
Arsenic47 SCC, BCC carcinoma, however, no specific HPV subtypes have been
Tobacco smoking48 SCC associated with non-melanoma skin cancer.
UV=ultraviolet. BCC=basal-cell carcinoma. SCC=squamous-cell carcinoma.
Although the association between warts and squamous-
PUVA=psoralen and UVA. cell carcinoma is well described, oncogenic HPV subtypes
are also present in 60% of basal-cell carcinomas from
Table 2: Environmental risk factors for non-melanoma skin cancers
immunosuppressed patients and 36% of basal-cell
carcinomas from immunocompetent patients, suggesting
equator. Gradients are similar for men and women, and that these viruses could be involved in development of
all ages.18 The thinner ozone layer and shorter distance basal-cell carcinoma.30 However, risk of squamous-cell but
traversed by UVB at lower latitudes than at high latitudes not basal-cell carcinoma is associated with seropositivity
make residents of these regions most vulnerable to the for HPV.31
effects of this radiation.19 An inverse association with The versatility of HPV in lesional, non-lesional, normal
latitude for both basal-cell and squamous-cell carcinoma sun-exposed, and non-sun-exposed skin suggests that
was shown in a survey of eight geographically diverse these viruses might be indirectly involved in pathogenesis

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of non-melanoma skin cancer by facilitating UV-related

carcinogenesis via mechanisms such as prevention of SHH
UV-induced apoptosis or impaired DNA repair.32 In this
context, psoralen and UVA (PUVA) therapy-induced
PTCH
immunosuppression could play an important part in
PUVA-related carcinogenesis by affecting extent and
pathogenicity of HPV infection.33
In white transplant recipients, risk of squamous-cell
SMO
carcinoma increases 65–250-fold and risk of basal-cell
carcinoma ten-fold to 16-fold compared with the non-
transplanted population.34,35 The ratio of squamous-cell to Cell
basal-cell carcinoma also reverses in iatrogenic immuno- membrane

suppression, because squamous-cell carcinomas occur COS-2

more frequently in transplant recipients than do basal-cell
Fu– GLI
carcinomas, whereas in the general population basal-cell
carcinoma is three to six times more frequent than are Nucleus GLI SUFU
squamous-cell carcinomas.36
Age, skin colour, male sex, UV dose, and duration of TGFβ
immunosuppression are key components in pathogenesis WNT
of post-transplant non-melanoma skin cancer. However, BMP
PTCH1/2
complex genetic factors affecting the extent and
consequences of immunosuppression can determine Figure 1: Sonic hedgehog signalling and pathogenesis of basal-cell carcinoma
individual risk.37 Patients with HIV/AIDS or non-Hodgkin SHH=sonic hedgehog. PTCH=patched. SMO=smoothened. Fu=fused. SUFU=suppressor of fused.
TGFβ=transforming growth factor β. WNT=wingless. BMP=bone morphogenetic protein. Reproduced from
lymphoma, specifically chronic lymphocytic leukaemia, reference 50 by permission of Blackwell Publishing.
also have aggressive squamous-cell carcinomas.38,39
Table 2 lists factors linked to development of non-
melanoma skin cancer.16,17,20–22,28–48 CDKN2A
Naevoid basal-cell carcinoma syndrome (Gorlin
syndrome), which is an autosomal dominant disorder TP53 GSTT1
–
with distinct morphological features including multiple – –
basal-cell carcinomas, results from germline mutations
in PTCH1, a segment polarity gene (9q22.3) originally Non-melanoma –
MC1R CYP2D6
identified in Drosophila melanogaster, which plays a crucial skin cancers
part in vertebrate development.49 PTCH1 has tumour
suppressor functions and encodes a 12-pass putative – +
–
transmembrane protein that acts like the receptor of the XPC Telomerase
diffusible morphogen protein, sonic hedgehog (figure 1).51
Loss of function mutations of PTCH1 result in reduced PTCH1
suppression of intracellular signalling by another
transmembrane protein, the G-protein-coupled receptor,
Figure 2: Major pathways involved in the pathogenesis of non-melanoma skin
smoothened (SMO). SMO targets the GLI family of cancers
transcription factors, and PTCH1 mutations result in Pathways exert unequal effects on pathogenesis of basal and squamous cell
sustained activation of target genes. Somatic PTCH1 carcinoma. CDKN2A=cyclin-dependent kinase inhibitor 2A.
GSTT1=glutathione S-transferase theta 1. CYP2D6=cytochrome P450, family 2,
mutations have a high frequency in familial basal-cell
subfamily D, polypeptide 6. PTCH1=patched homolog 1. XPC=xeroderma
carcinoma,52 and are present in up to 68% of sporadic pigmentosum, complementation group C. MC1R=melanocortin 1 receptor.
basal-cell carcinomas.53 Pathogenesis of basal-cell TP53=tumour protein 53.
carcinoma in naevoid basal-cell carcinoma syndrome is
due to a spontaneous defect in maintenance of epidermal they might be important independent risk factors for
homoeostasis and an intrinsic property of the cells that is non-melanoma skin cancer.56,57 UVB and UVC radiation
independent of external mutagenic stress, such as short- result in DNA damage, leading to production of signature
wavelength UVB.54 PTCH1 loss has also been reported as cyclobutane-type pyrimidine dimers, which activate
an early event in pathogenesis of squamous-cell mechanisms for removal of damaged DNA, a delay in
carcinoma.55 Figure 2 shows the major pathogenic cell-cycle progression, DNA repair, or apoptosis by
pathways involved in non-melanoma skin cancer. transcriptional activation of TP53 and related genes such
The melanocortin-1 receptor (MC1R) gene variants as CDKN1A, BCL2, and BAX.58,59
ASIP and TYR are associated with fair skin, red hair, and Signature UV-DNA lesions are repaired via the
increased melanoma risk, and evidence suggests that nucleotide excision repair pathways, which can be

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 Seminar
subdivided into transcription-coupled repair and global
genome repair. The XPC protein is specific to the genome
repair pathway, and recognises helix-distorting lesions
and starts their repair. Inactivating XPC mutations are
associated with xeroderma pigmentosum, a rare
autosomal recessive syndrome in which several skin
cancers—especially squamous-cell carcinoma—are
seen.60 Keratinocytes from DNA repair-deficient patients
are more prone to apoptosis than are those with normal
DNA repair capacity.61
Inactivation of the TP53 tumour suppressor gene has
an important role in induction of non-melanoma skin
cancer by UV radiation, and transcription factor P53 is
often mutated in this disease. P53 mutation renders cells
resistant to apoptosis, resulting in the clonal expansion
of precancerous keratinocytes. Roughly 90% of
squamous-cell and 50% of basal-cell carcinomas have a
P53 mutation.59,62,63 Additionally, inactivation of the
CDKN2A locus (encoding a cell-cycle inhibitor protein)
has been detected in squamous-cell carcinomas from
patients with xeroderma pigmentosum and sporadic
non-melanoma skin cancer.64,65
The cytochrome P450 (CYP) supergene family has more
than 30 isoforms, which catalyse biotransformation of
several xenobiotics, often as the first step of a two-phase
detoxification. The resulting highly reactive intermediate
serves as a substrate for phase-two enzymes, including
members of the glutathione S-transferase (GST) supergene
family. GSTs can also catalyse detoxification of the products
of oxidative stress (eg, lipid and DNA hydroperoxides).
Polymorphisms in GSTT1 and CYP2D6 are associated
with susceptibility to non-melanoma skin cancer, and
polymorphisms in CYP2D6 (together with vitamin D
receptor and tumour necrosis factor α) with increasing
tumour numbers.66,67 Additionally, some allelic variants of
CYP2D6 are associated with a multiple presentation
phenotype of basal-cell carcinoma.68
Features
Xeroderma pigmentosum Autosomal recessive; multiple epidermal skin cancers in childhood; increased
susceptibility to DNA damage; abnormal DNA base excision repair
Albinism Part or complete failure to produce melanin in the skin and eyes
Muir-Torre syndrome Autosomal dominant; germline mutations in genes involved in DNA mismatch
repair; sebaceous neoplasms in association with internal malignancy
KID (keratosis, icthyosis, Development of invasive squamous-cell carcinoma within dysplastic lesions
deafness)
Dystrophic epidermolysis Autosomal recessive mechano-bullous disorder; mutations in the human type VII
bullosa collagen gene (COL7A1)
Fanconi anaemia Autosomal recessive; congenital malformations; bone-marrow failure;
development of squamous-cell carcinoma and other cancers
Rothmund-Thompson Autosomal recessive; progressive poikiloderma including alopecia, dystrophic
syndrome teeth and nails, juvenile cataracts, short stature, hypogonadism, and bone defects
Werner syndrome Early ageing; excess cancer risk; high incidence of type 2 diabetes mellitus; early
atherosclerosis; ocular cataracts; osteoporosis
Others Hereditary non-polyposis coli; dyskeratosis congenita; Huriez syndrome;
Li–Fraumeni syndrome; chronic mucocutaneous candidiasis
Table 3: Syndromes predisposing to cutaneous squamous-cell carcinoma
676
Human telomerase is a unique enzyme that uses RNA
as a template to add telomere repeats at chromosome
ends to compensate for telomere loss during cell division.
Unlike healthy cells, most immortal and tumour cells
have substantial telomerase activity and show no net loss
of telomere length during proliferation. Therefore,
telomerase reactivation in cells results in tumour
immortalisation.69 Investigators have shown telomerase
activation to be important in pathogenesis of basal-cell
and squamous-cell carcinoma.70,71 Table 3 lists syndromes
predisposing to squamous-cell carcinoma.
Diagnosis
Early basal-cell carcinomas are usually small, translucent,
or pearly, with raised telangiectatic edges. Roughly 80%
of all basal-cell carcinomas occur on the head and neck,
and clinical diagnosis is fairly straightforward.72 In
addition to the classic rodent ulcer with an indurated
edge and ulcerated centre, nodular or cystic, superficial,
morphoeic, and pigmented basal-cell carcinomas are
other common subtypes (figure 3). 10–40% of basal-cell
carcinomas contain a mixed pattern of two or more of
these histological subtypes, drawing attention to the need
for a clinicopathological diagnosis.73,74 By contrast with
nodulocystic basal-cell carcinoma—which is the most
common subtype, usually presenting on the head and
neck—superficial basal-cell carcinomas predominantly
present on the trunk. Superficial basal-cell carcinomas
can sometimes be difficult to differentiate from psoriasis,
discoid eczema, or Bowen’s disease, and pigmented and
nodular subtypes can cause diagnostic confusion with
melanoma. 5% of all basal-cell carcinomas are morphoeic
lesions, which have ill-defined borders, can be difficult to
diagnose clinically, and often present late.75 Midfacial
basal-cell carcinomas have been suggested to occur on
embryonic fusion planes—a notion that has been
challenged.76,77 Patients with initially truncal basal-cell
carcinomas of superficial histology have the highest rate
of increasing carcinoma numbers.78
Unlike basal-cell carcinoma, squamous-cell carcinomas
can have precursor lesions, such as actinic keratoses and
squamous-cell carcinoma in situ (Bowen’s disease;
figure 4), which are considered premalignant.79 Although
the rate of progression of individual actinic keratoses to
invasive squamous-cell carcinoma has been estimated as
1–10% over 10 years, this risk could be much higher in
patients with more than five actinic keratoses.80,81
Presence of actinic keratoses is an important marker of
high UV exposure and increased risk of non-melanoma
skin cancer generally.82 This marker can sometimes
allow early identification and treatment of in-situ
squamous-cell carcinoma to avoid metastasis and tissue
destruction, since squamous-cell carcinomas are more
invasive than are basal-cell carcinomas.
Squamous-cell carcinoma usually develops on sun-
exposed sites because of photodamage of the skin. Lesions
of Bowen’s disease usually present as slowly enlarging
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A B
D E
Figure 3: Clinical subtypes of basal-cell carcinoma
(A) Classic rodent ulcer. (B) Nodular or cystic. (C) Superficial. (D) Morphoeic. (E) Pigmented basal-cell carcinoma.
erythematous scaly or crusted plaques and have a 3–5%
risk of progression to squamous-cell carcinoma.83
Keratoacanthomas (figure 4) are characterised by rapid
onset, progression, and regression within months, and
can have clinical and histological similarities to well
differentiated squamous-cell carcinoma.84 Induration is a
common feature of all squamous-cell carcinomas and is
usually the first sign of malignancy. The typical lesion has
an adherent crust and ill-defined edges, indicating spread
beyond visible margins (figure 4).
In case of diagnostic confusion, a confirmatory
diagnosis can be achieved by histopathological
examination, which remains the gold standard for
diagnosis of non-melanoma skin cancer. The UK Royal
College of Pathologists’ minimum dataset for the
histopathological reporting of basal-cell carcinoma
includes growth patterns (nodular, superficial, infiltrative
or morphoeic, and micronodular types), differentiation
of severely atypical or malignant squamous type
(basosquamous carcinoma), and involvement or
clearance of deep and peripheral margins.85 Similarly,
the histological report for squamous-cell carcinoma
should include pathological pattern, morphological
changes to cells, degree of differentiation, histological
grade, depth, extent of dermal invasion, and presence of
perineural, vascular, or lymphatic invasion.86
As further novel non-invasive therapeutic modalities
for non-melanoma skin cancers become available,
interest in non-invasive screening and diagnosis of these
lesions has also increased. Dermoscopy (dermatoscopy)
with cross-polarised light, high-frequency (20–100 MHz)
ultrasound, optical coherence tomography with infrared
light, and in-vivo confocal microscopy have been used for
early diagnosis of non-melanoma skin cancer.87 The
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C
technique of fluorescence lifetime imaging generates
image contrast between different states of tissue because
of differences in fluorescence decay rates, and has a
potential clinical role in imaging of basal-cell carcinoma.88
Besides dermoscopy—which is a useful diagnostic aid
for pigmented lesions—clinical applications of other
non-invasive diagnostic techniques for non-melanoma
skin cancers have not yet been defined.
Prognosis and staging
Non-melanoma skin cancers, especially basal-cell
carcinomas, have low metastatic potential and are
associated with low mortality. The likelihood of
metastases and recurrence of squamous-cell and basal-
cell carcinoma depends on several prognostic indicators
(table 4).86,89–91 These indicators draw attention to the
importance of a detailed pathological description, since
individual lesion and host characteristics have to be
taken into account when determining the prognosis of
non-melanoma skin cancer.
In addition to the factors outlined in table 4, incomplete
excision should be considered a poor prognostic indicator
for both basal-cell and squamous-cell carcinomas, since
patients with an inadequately excised lesion are at risk of
local recurrence. Additionally, patients with squamous-
cell carcinoma are at risk of developing subsequent nodal
metastases, and this risk is most pronounced in patients
with recurrent disease.89,90 Tumour thickness of more
than 6 mm and desmoplasia independently affect risk of
local recurrence of squamous-cell carcinoma.91 Routine
sentinel-lymph-node biopsy is not justified in patients
with high-risk squamous-cell carcinoma—a notion that
is lent support by most guidelines for management of
this disease.86,92 Mucosal–cutaneous junctional and
677
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A B
C D
Figure 4: Clinical appearance of squamous-cell carcinoma and precursor lesions
(A) Actinic keratosis. (B) Squamous-cell carcinoma in situ (Bowen’s disease). (C) Keratoacanthoma.
(D) Squamous-cell carcinoma.
mucosal squamous-cell carcinomas have a worse
prognosis than does cutaneous disease.
Perineural invasion is an infrequent complication of
squamous-cell (2·5–14·0%) and basal-cell (3%) carcinomas,
and is associated with high risk of recurrence and
metastases and risk of significant clinical morbidity due to
neurological deficits.93 Treatment of these patients remains
challenging, since the role of adjuvant radiotherapy has
not yet been defined.94 Patients with non-melanoma skin
cancer have a ten-fold increased risk of developing a
subsequent non-melanoma skin cancer and non-cutaneous
678
malignancy compared with the general population, and
this risk diminishes with increasing age at diagnosis of
first non-melanoma skin cancer.95
In view of the rarity of nodal and visceral metastases in
basal-cell carcinoma (1:50 000), clinical and pathological
staging is seldom done. The TNM system, recommended
by the American Joint Committee on Cancer, is a staging
system for all histological types of skin cancer but is
most often used for staging squamous-cell carcinoma
(panel 1). Because of its deficiencies and failure to
recognise several of the well known prognostic indicators
for squamous-cell carcinoma, this staging system has
often been criticised.89,96,97
Treatment
Management
The British Association of Dermatologists has issued
guidelines for management of non-melanoma skin
cancers.86,98 Interventions for management of basal-cell
carcinomas in immunocompetent patients and
prevention of non-melanoma skin cancers in high-risk
groups have been systematically reviewed.99,100 Routine
use of sunscreen might prevent squamous-cell
carcinoma, but is of unproven benefit in basal-cell
carcinoma.101 Several government and charitable
organisations have launched prevention programmes
for skin cancer targeting excessive sun exposure as the
most important pathogenic factor.102,103 The main
messages of these programmes are to restrict time in
midday sun, watch the UV index, stay in the shade, use
topical sunscreens, wear protective clothing, and avoid
sunlamps and tanning parlours.103
The primary aim of treatment is complete removal or
destruction of the lesion while achieving a good and
acceptable cosmetic outcome as an important secondary
goal. Choice of treatment depends on several factors,
including clinical and histological nature, size, and site
of the lesion; comorbidities; local expertise; availability;
and treatment costs. The National Institute for Health
and Clinical Excellence and National Collaborating
Centre for Cancer have recommended that cancer
networks establish two levels of multidisciplinary teams:
a local hospital skin-cancer team and a specialist skin-
cancer team.104
Histological examination of excisional margins is
usually necessary to ensure complete removal of non-
melanoma skin cancer, but not all surgical techniques
allow this assessment. Often, clinical judgment alone is
applied when destructive surgical techniques are used.
Unfortunately, such techniques frequently result in a
poor cosmetic outcome. The continuing search for tissue-
sparing and non-surgical treatments has led to
development of several non-invasive and novel
experimental treatment modalities for basal-cell
carcinoma. However, for basal-cell carcinoma, and more
so for squamous-cell carcinoma, surgical excision or
destruction is still the mainstay of treatment. Treatments
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for non-melanoma skin cancer can be broadly classified
into surgical and medical (panel 2).
Surgical treatments
Excision with predetermined margins is one of the most
common and effective treatment strategies for well
defined basal-cell carcinoma and most squamous-cell
carcinomas. Unlike many other destructive surgical
techniques, it allows for histological examination of the
excised tissue and accurate assessment of excisional
margins. A 4–5 mm surgical margin ensures peripheral
clearance in roughly 95% of well defined small basal-
cell and squamous-cell carcinomas.105 By contrast,
treatment of morphoeic or large basal-cell carcinoma
needs a 3–15 mm margin to obtain a similar clearance
rate.105 For large and high-risk squamous-cell carcinomas,
an excision margin of greater than 6 mm with
histological examination of tissue margins or Mohs
micrographic surgery is recommended.86 The
recommended excision margins vary between guidelines
issued by professional organisations in different
countries. Apart from being highly effective (recurrence
rate of <2% in 5 years after histologically complete
excision of basal-cell carcinoma), excision is usually
associated with a good cosmetic outcome.106,107
Since recurrent basal-cell carcinoma is associated with
poor cure rates after excision, a 5–10 mm excision margin
is recommended. Treatment options for incompletely
excised basal-cell carcinomas include immediate
retreatment, especially when dealing with high-risk
disease at crucial midfacial sites (in which the deep
surgical margin is often involved). Other problematic
lesions are those that have been treated with complex
surgical procedures (eg, flaps or grafts), and incompletely
excised low-risk primary tumours with possible lateral
margin involvement.98 Most authorities recommend re-
excision of incompletely excised basal-cell carcinomas,
with or without frozen-section control or with
histologically controlled margins.98,108,109 However, adjuvant
radiotherapy for postsurgical histologically involved
margins can be an acceptable alternative when further
excision would be difficult.
The primary aim of Mohs micrographic surgery is to
identify and excise the entire tumour and its residues to
ensure complete resection. As a result, 5-year cure rates
of up to 98·9% have been reported for both primary and
recurrent basal-cell and squamous-cell carcinoma, with
the additional benefit of preservation of healthy peripheral
skin.110,111 Main indications for this procedure are
centrofacially located tumours, large tumours, morphoeic,
infiltrative, micronodular, or basosquamous basal-cell
carcinoma, poorly defined tumour margins, recurrent
lesions, and those with perineural or perivascular
involvement.98 Apart from availability of skilled
practitioners, setting up of a service for this surgery has
financial and resource-related implications that can be
limiting factors in this context.
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Basal-cell carcinoma Squamous-cell carcinoma
Clinical subtype Morphoeic ··
Tumour size >5 cm (giant) > 2 cm
Tumour depth + >2 mm*
Tumour site Centrofacial and ears At sites of radiation, thermal damage,
ulceration, sinuses, inflammation, scars or
Bowen’s disease, non-exposed sites, ear, lip,
sun-exposed sites excluding lip and ear
Histological subtype Infiltrative and Spindle cell (carcinosarcomas),
micronodular acantholytic, desmoplastic
Histological features of aggression Perineural or perivascular Broders’ grades 3 and 4, perineural
involvement, or both involvement
Host immunosuppression + +
Recurrent lesions + +
Lymph-node involvement or + +
distant metastasis
*Squamous-cell carcinoma greater than 2·0 mm in thickness, and especially those greater than 6·0 mm, are associated
with high risk of metastasis and local recurrence.89
Table 4: Factors indicating poor prognosis in non-melanoma skin cancer86,89–91
Investigators comparing quality-of-life measurements
for patients who underwent different surgical treatments
reported that excision and Mohs micrographic surgery
equally improved all quality-of-life domains.112 In a
randomised controlled trial,113 recurrence of primary facial
basal-cell carcinoma did not differ after Mohs micrographic
surgery or surgical excision, but there were significantly
fewer recurrences of recurrent facial basal-cell carcinoma
after Mohs micrographic surgery than after excision.
After surgical excision, curettage and electrodesiccation
(curettage and cautery) is the second most common
surgical procedure for treatment of basal-cell carcinoma
in the UK.114 5-year cure rates of up to 92·3% have been
achieved for selected primary basal-cell carcinomas with
this procedure.115 Indications include low-risk lesions at
sites other than the head and neck, although very high
cure rates have been obtained when treating primary non-
fibrosing basal-cell carcinoma at facial sites of medium to
high risk.116 However, number of cycles used can vary and
several modified techniques exist, so comparison of this
procedure with other treatment modalities is difficult. As
with other destructive surgical techniques, curettage and
electrodesiccation should not be considered for treatment
of recurrent or ill-defined tumours or for high-risk
histological subtypes of basal-cell carcinoma.98
Curettage and electrodesiccation of small, well
differentiated, primary slow-growing squamous-cell
carcinoma, can also achieve excellent results.115 Long-term
follow-up studies and those investigating treatment of
large squamous-cell carcinomas and different subtypes of
squamous-cell carcinoma have not been undertaken with
this procedure. Curettage and electrodesiccation is not
recommended for treatment of recurrent disease.86
Compared with surgical excision and Mohs micrographic
surgery, curettage and electrodesiccation did not improve
tumour-related quality of life.116
679
 Seminar
Panel 1: American Joint Committee on Cancer staging
system for cutaneous basal-cell and squamous-cell
carcinoma of the skin (excluding eyelid, vulva, and penis)
Primary tumour (T)*
TX: Primary tumour cannot be assessed
T0: No evidence of primary tumour
Tis: Carcinoma in situ
T1: Tumour 2 cm or less in greatest dimension
T2: Tumour 2–5 cm in greatest dimension
T3: Tumour more than 5 cm in greatest dimension
T4: Tumour invades deep extradermal structures (ie, cartilage,
skeletal muscle, or bone)
Regional lymph nodes (N)
NX: Regional lymph nodes cannot be assessed
N0: No regional lymph node metastasis
N1: Regional lymph node metastasis
Distant metastasis (M)
MX: Distant metastasis cannot be assessed
M0: No distant metastasis
M1: Distant metastasis
Stage grouping
Stage 0: Tis, N0, M0
Stage I: T1, N0, M0
Stage II: T2, N0, M0; T3, N0, M0
Stage III: T4, N0, M0; any T, N1, M0
Stage IV: any T, any N, M1
Histopathologic grade (G)
GX: Grade cannot be assessed
G1: Well differentiated
G2: Moderately differentiated
G3: Poorly differentiated
G4: Undifferentiated
*For several simultaneous tumours, the tumour with the highest T category will be
classified and the number of separate tumours given in parentheses—eg, T2 (5).
Cold-induced destruction of non-melanoma skin cancer
can be achieved with liquid nitrogen cryosurgery. Several
variations in spray technique and duration and number of
freeze/thaw cycles have been used to improve results.117
This technique is considered appropriate for treatment of
low-risk primary basal-cell and squamous-cell carcino-
mas.86,98 Recurrence rates were similar for cryosurgery and
surgical excision in one study,118 and results of another
study119 showed a higher recurrence rate for basal-cell
carcinoma treated with cryosurgery (39%) than for
carcinoma treated with radiotherapy (4%) at 2-year follow-
up. Cosmetic results were similar for cryosurgery and
radiotherapy, whereas results of surgical excision were
better than were those of cryosurgery.118,119
Precise ablation of the tumour can be readily achieved
with a carbon dioxide (CO2) laser. Although laser treatment
of non-melanoma skin cancer has rarely been studied,
successful use of pulsed CO2 laser in treatment of
680
Panel 2: Treatments for non-melanoma skin cancer
Surgical (physical)
• Excision
• Curettage and electrodesiccation
• Cryosurgery
• Mohs micrographic surgery
• Radiotherapy
• Erbium: yttrium-aluminum-garnet laser ablation,
carbon dioxide laser vaporisation
Non-surgical (medical)
• Topical fluorouracil*
• Topical imiquimod*
• Photodynamic therapy (systemic or topical)*
• GDC-0449*†
• Intralesional interferon alfa-2b†
• Ingenol mebutate,*† cyclophilin*†
• Histone deacetylase inhibitors (valproic acid, vorinostat)†
*Not recommended for treatment of squamous-cell carcinomas. †Drugs under
investigation.
superficial basal-cell carcinoma has been described.120
Another study121 reported a clinical and histopathological
cure in 140 patients with superficial and nodular basal-
cell carcinoma treated with superpulse CO2 laser, with no
recurrences at a 3-year follow-up. As with other ablative
therapies, histological confirmation of cure is not possible
with CO2 laser ablation, therefore use should be restricted
to low-risk basal-cell carcinoma. Flashlamp-pumped
pulse dye laser is effective in treatment of superficial
basal-cell carcinoma.122
Superficial and electron beam radiotherapy and
brachytherapy are effective adjuvant therapeutic strategies
for treatment of primary and surgically recurrent basal-
cell carcinoma.98,123,124 These methods have even been
suggested as the treatment of choice for high-risk non-
melanoma skin cancer in patients who are unwilling or
unable to tolerate surgery.85,97,123 Radiotherapy can be used
as a palliative modality to improve quality of life of patients
with advanced or incurable disease.125
Results of a randomised controlled trial126 comparing
surgical excision with use of frozen section margin control
with radiotherapy for basal-cell carcinoma showed that
persistent tumours and recurrences were most common
in the radiotherapy group. Some patients develop
dyspigmentation, telangiectasia, and radiodystrophy at
sites treated with radiotherapy, resulting in a poor cosmetic
outcome.126,127 Furthermore, radiotherapy is contraindicated
in treatment of basal-cell carcinomas that have recurred
after radiotherapy.98 Modifications in radiotherapy
techniques have successfully overcome issues with
cosmesis and effiacy.128
In squamous-cell carcinoma of the lip, nasal vestibule,
and ear, radiotherapy can provide the best cosmetic and
functional result.86 Additionally, long-term results of
squamous-cell carcinoma treated with radiotherapy are
www.thelancet.com Vol 375 February 20, 2010

similar to those of other treatment modalities.115,127
Radiotherapy adjuvant to surgery offers the best chance
of achieving locoregional control in head and neck nodal
metastases from squamous-cell carcinoma.129 Risk of
latent non-melanoma skin cancer and other skin cancers
after 15–20 years of exposure suggests that radiotherapy
should be used cautiously in young patients (aged
<65 years).130 Patients with naevoid basal-cell carcinoma
syndrome have increased sensitivity to radiation and a
tendency to develop several basal-cell carcinomas in the
irradiated field; radiotherapy is therefore also
contraindicated in these patients.131
Medical treatments
Fluorouracil is an antineoplastic antimetabolite that
disrupts DNA and RNA synthesis by inhibiting the enzyme
thymidylate synthetase, thereby preventing purine and
pyrimidine from becoming incorporated into DNA during
the S-phase of the cell cycle.132 It has been established as a
topical treatment for actinic keratoses and Bowen’s disease
since the late 1960s but is rarely used to treat basal-cell
carcinoma, even though high histological cure rates and
good cosmetic results have been reported with topical
fluorouracil treatment of small and superficial basal-cell
lesions.133 Local irritation, erythema, swelling, desquama-
tion, and tenderness are common treatment-site reactions.
Topical fluorouracil is not recommended for squamous-
cell carcinoma, and high recurrence rates (21·4%) reported
at 10-year follow-up suggest that this treatment is not
appropriate for nodular basal-cell carcinoma.134
Imiquimod is a synthetic immune response modifier
belonging to the imidazoquinolone family. It acts by
stimulating toll-like receptor 7, which is expressed on
dendritic cells and monocytes, leading to increased
production of cytokines and chemokines, which in turn
promote both T-helper-1 innate and adaptive cell-mediated
immune responses.135 Topical 5% imiquimod cream is an
emerging non-invasive therapeutic option for superficial
and nodular basal-cell carcinoma. A 69–100% response
rate for superficial basal-cell carcinoma, and 42–76% for
nodular disease, has been reported for once daily, five
times per week treatment for 6 weeks with topical 5%
imiquimod cream.136,137 Similar response rates have been
shown in two 5-year follow-up studies138,139 investigating
imiquimod treatment of superficial basal-cell carcinoma,
suggesting that clinical assessment of the initial response
is predictive of outcome in the long term. Long-term
follow-up studies for imiquimod treatment of nodular
basal-cell carcinoma are scarce, but results from a phase 3
clinical trial suggest that imiquimod applied three times
per week for 8–12 weeks has only slight activity against
small nodular lesions. This finding could be confirmed by
histopathological analyses of treatment sites, which
showed presence of residual tumour in more than a third
of treated patients.140 Local skin reactions including
erythema, oedema, pruritus, erosion, ulceration,
dyspigmentation, and scabbing are common side-effects.
www.thelancet.com Vol 375 February 20, 2010
Seminar
Photodynamic therapy refers to activation of a topically
applied or systemically delivered photosensitiser in
neoplastic or dysplastic tissue, by light of appropriate
wavelength and in the presence of oxygen. This process
leads to the production of reactive oxygen species,
especially singlet oxygen, which modify cellular functions
or result in cell death by necrosis or apoptosis, thus
promoting tumour destruction.141 Topical methyl
aminolevulinate and 5-aminolevulinic acid photodynamic
therapy are effective treatments for superficial basal-cell
carcinoma.142 Results of a study directly comparing these
two photosensitisers in treatment of nodular basal-cell
carcinoma showed no difference in efficacy.143 Further
research has shown that photodynamic therapy could be
an effective treatment for nodular basal-cell carcinoma,
and that previous debulking of the tumour with curettage
and routine double photodynamic therapy or fractionation
of light can improve clearance rates.142,144,145
Results of a 5-year follow-up study comparing surgical
excision with methyl aminolevulinate photodynamic
therapy show a significantly higher lesional recurrence
rate (4% vs 14%) but a much better cosmetic outcome for
photodynamic therapy than for surgical excision.146 Other
investigators have also shown surgical excision to be more
effective than is fractionated illuminated 5-aminolevulinic
acid photodynamic therapy for treatment of nodular basal-
cell carcinoma, with a 3-year recurrence rate much higher
in the photodynamic therapy group (30·3%) than in the
surgical excision group (2·3%).147 For patients with
superficial basal-cell carcinoma, methyl aminolevulinate
photodynamic therapy has a similar response to that of
cryosurgery at 3-month and 5-year follow-up. Cosmetic
outcome was best for photodynamic therapy.148
Since data are scarce for the efficacy of topical
photodynamic therapy in primary cutaneous invasive
squamous-cell carcinoma, topical therapy cannot be
recommended for this subtype of non-melanoma skin
cancer.142 The main side-effects are burning or stinging
pain during light exposure, post-treatment ery-
thema, oedema, and temporary postinflammatory
Photoactivatable
COX inhibitors Immune response Cyclopamin Retinoids
porphyrins
Hedgehog
COX-2 Immunosuppression Apoptosis signalling AP1
Intracellular
ROS
pathway
Tumour growth
Figure 5: Pathogenesis-oriented therapeutic approaches for non-melanoma skin cancer
COX=cyclo-oxygenase. AP1=activator protein 1. ROS=reactive oxygen species. Reproduced from reference 154
with permission of Blackwell Publishing.
681
 Seminar
hypopigmentation or hyperpigmentation. In addition to
topical therapy, systemic photodynamic therapy with
intravenous porfimer has been tested as treatment for
basal-cell carcinoma. Cure rates of 50–100% have been
reported, which might be most appropriate for
individuals presenting with several basal-cell carcinomas
or naevoid basal-cell carcinoma syndrome.149,150
Perilesional and intralesional interferon alfa-2b
treatment of basal-cell carcinoma has been associated with
high cure rates (approaching 98% at 12 years) and good
cosmetic outcomes. However, the main limiting factors of
this treatment are many treatment sessions, necessitating
frequent office visits, and high treatment costs.151
Non-invasive treatment options for non-melanoma skin
cancer are increasingly being explored. Safety and efficacy
of several treatments are under investigation. Solasodine
glycosides are naturally occurring glycoalkaloids found in
plants of the nightshade family—eg, aubergine. In a cream
formulation, 0·005% solasodine glycosides (containing
mainly solasonine and solamargine) are effective in
treatment of basal-cell carcinoma.152 A novel iron-chelating
agent, CP94 (1,2-diethyl-3-hydroxypyridin-4-one hydrochlo-
ride), added to topical 5-aminolevulinic acid temporarily
increases accumulation of photosensitiser in the tumour
and achieves significantly greater clearance rates in nodular
basal-cell carcinoma than does 5-aminolevulinic acid
photodynamic therapy alone.153
Other investigational agents for treatment of actinic
keratoses and basal-cell carcinoma are tazarotene,
cidofovir, ingenol mebutate, cyclopamin, calcium
dobesilate, and histone deacetylase inhibitors such as
valproic acid, vorinostat, and GDC-0449 (figure 5,
panel 2). Further studies are needed to ascertain the
efficacy and adverse-effect profiles of these treatments.
Capecitabine, an oral selective fluorouracil precursor, is
metabolised to fluorouracil within tumour cells,
providing the advantage of being selectively uptaken at
the tumour site with subsequent sustained exposure of
the tumour cells to fluorouracil. Reports of inflammation
of actinic keratoses during capecitabine treatment
suggest that this drug could have a role in treatment of
actinic keratoses and other non-melanoma skin
cancers.155
Our understanding of the pathogenesis of non-melano-
ma skin cancers—and especially basal-cell carcinoma—has
improved substantially in recent decades. Improvement
has been associated with development of newer non-
invasive treatments, such as photodynamic therapy and
topical imiquimod, which have become established in the
treatment of some basal-cell carcinomas and premalignant
skin lesions. For most non-melanoma skin cancers,
however, conventional surgical and destructive treatments
remain the first-choice treatment strategies. Coupled with
adequate sun-avoidance advice, behavioural modification,
and sun-protection education, new non-invasive treatment
approaches are a welcome addition to the management of
the most common human cancers.
682
Contributors
All authors contributed to the search of published work and took part in
writing the first draft and subsequent versions of the report.
Conflicts of interest
VM declares that he has no conflicts of interest. JTL has received
honoraria for presentations and research funding from 3M Healthcare,
Galderma, LEO, Novartis, Shire, Stiefel, and Almirall. R-MS has received
honoraria for presentations and research funding from Almirall-Hermal,
Biocam, Energist, Galderma, Intendis, Meda, Photocure, Photonamic,
Waldmann Medizintechnik, and 3M Healthcare, and is a member of the
advisory boards of Galderma, Peplin, and Intendis.
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