Squamous Cell Carcinoma of Skin: A Brief Review
Review
Squamous Cell Carcinoma of Skin: A brief review
Siavash Rahimi
Consultant Histopathologist, Pathology Centre, Queen Alexandra Hospital, Southwick Hill Road, Cosham, Portsmouth PO6 3LY
Abstract
Cutaneous squamous cell carcinoma (SCC) is the second most
common skin cancer in Caucasians, most frequently occurring on
sun-exposed areas of the body. Most SCCs are treated surgically, either
by excision or Mohs micrographic surgery. Despite the large amount
of English literature with regard to cutaneous SCC in many instances
the surgical treatment is not appropriate resulting in recurrences and/
or metastasis. The following brief review highlights the histology,
molecular biology and surgical treatment of skin SCC. Clin Ter 2013;
164(2):143-147. doi: 10.7417/CT.2013.1534
Key words: cancer, review, skin, SCC
Introduction
Primary cutaneous squamous cell carcinoma (SCC) is a
malignant tumour that arises from the keratinising cells of
the epidermis or its appendages. It is locally invasive and
has the potential to metastasise to other organs of the body
(1). Skin SCC are the most common cancers diagnosed and
incidence is rising across the world (2) and, together with ba-
sal cell carcinoma, constitutes about 20% of non melanoma
skin cancers. There is a rising incidence with age and the
incidence is higher in Caucasians and men, probably because
of greater head and neck exposure to ultraviolet radiation
(UVR) (2, 3). About 70% of SCCs appear on the skin of the
head and neck (1). The development of cutaneous SCC is
strongly associated with sun exposure (4). The evolution of
SCC on sun-exposed areas is a multistep process triggered by
UVR, in which precursor lesions exist. However, the exact
classification of the various lesions in this process, mainly
actinic keratosis (AK), is still disputed, and its pathogenesis
requires further clarification. AK is considered by some as a
premalignant lesion and by others as being one type of SCC
(4, 5). The more sun exposed areas differ somewhat between
men and women. In men these are face, backs of hands,
head and ears particularly. In women these are face, backs
of hands, lower legs, anterior neck and chest. Other risk
Correspondence: Siavash Rahimi MD, Consultant Histopathologist, Pathology Centre, Queen Alexandra Hospital, Southwick Hill Road
Cosham, Portsmouth PO6 3LY. Tel +44 02392 286098. E-mail: rahimi.siavash@gmail.com; siavash.rahimi@porthosp.nhs.uk
Copyright © Società Editrice Universo (SEU)
143
Clin Ter 2013; 164 (2):143-147. doi: 10.7417/CT.2013.1534
factors are chemical carcinogens (arsenic and chromium)
(6), Soot (scrotal cancers in chimney sweeps), Tar, pitch oils,
human papilloma virus infection (HPV), ionising radiation
exposure, chronic inflammation, skin near chronic ulcers
(Marjolin’s ulcers) and around chronic sinuses (for example
osteomyelitis) and lupus vulgaris. The host responses and
susceptibility to UVR like fair skin, blonde or red hair, play
an important role in SCC cancerogenesis.
Genetic conditions such as xeroderma pigmentosum and
albinism are considered as risk factors. Pre-malignant con-
ditions, e.g., Bowen disease (BD), AK and keratoacantoma
may progress to squamous cell carcinoma.
The high risk SCC is defined as a lesion which have a
high recurrence rate after treatment and may metastasise.
The factors which affecting metastatic potential of cu-
taneous SCC are:
– Site: tumour arising at sun-exposed sites excluding lip
and ear, scalp, tumours arising in non-sun-exposed sites
(e.g. perineum, sacrum, penis, sole of foot) and areas
of previous injury e.g. burns, irradiation and chronic
ulcers.
– Diameter: tumours greater than 2 cm in diameter are
twice as likely to recur locally and three times as likely
to metastasise.
– Depth: tumours greater than 4 mm in depth (excluding
surface layers of keratin) or extending down to the sub-
cutaneous tissue (Clark level V).
– Perineural invasion.
The histological differentiation is also an important fac-
tor. Poorly differentiated tumours have a poorer prognosis,
with more than double the local recurrence rate and triple
the metastatic rate of better differentiated SCC. Locally re-
current disease itself is a risk factor for metastatic disease.
Other risk factors are immunosuppression and a pre-
viously treated lesion.
There are a number of diseases which should be dif-
ferentiated from SCC. Keratoacanthoma (can be difficult
to differentiate even histologically), basal cell carcinoma,
malignant melanoma (particularly amelanotic type), AK,
pyogenic granuloma, seborrhoeic warts, plantar warts or
verrucas.
144
The prognosis of cutaneous SCC can vary with age, de-
gree of sun exposure and other diseases coexisting with the
SCC. Early stage tumours will have a better than 90% five
year survival. Patients with metastatic lymph node disease
have around a 30% five year survival.
Histological subtypes
Acantholytic squamous cell carcinoma
Acantholytic squamous cell carcinoma (ASCC) is a
histological variant of cutaneous SCC which accounts for
2-4% of all cutaneous SCC (7-10). Histologically, there is
loosening of the intercellular bridges resulting in acantho-
lysis. These tumours may be in situ or invasive.
Acantholytic foci may also produce a pseudovascular
pattern mimicking angiosarcoma (pseudovascular SCC)
(11-13). The tumour involves predominantly the skin of the
head and neck region, particularly on and around the ears
(7-10). Typical features of squamous malignancy are iden-
tified including dyskeratosis, keratinocytic atypia, altered
maturation within the epithelium, and increased typical and
atypical mitotic figures. The behaviour of this tumour may
be more aggressive than conventional SCC (7-9, 14-16).
Spindle-cell squamous cell carcinoma
This is an uncommon variant of squamous cell carcino-
ma that exhibits a prominent spindle cell morphology. The
incidence of this variant may be higher in immunosuppressed
patients. It may be composed entirely of spindle cells, or
have a variable component of more conventional squamous
cell carcinoma.
The spindle cells have a large vesicular nucleus and
scanty eosinophilic cytoplasm, often with indistinct cell
borders. There is variable pleomorphism, usually with many
mitoses. Some tumours may coexpress cytokeratin and vi-
mentin, suggesting metaplastic change to a neoplasm with
mesenchymal characteristics (17). These tumours account
for slightly over one-third of cutaneous SCC (14).
Verrucous squamous cell carcinoma
Verrucous squamous cell carcinoma is a rare variant
of well-differentiated squamous cell carcinoma with low
malignant potential. Verrucous carcinoma comprises 2-12%
of all oral carcinomas, and is found predominantly in men
(18). Common sites include buccal and retromolar mucosa,
gingiva, floor of mouth, tongue and hard palate. They also
arise on the soles, rarely the palms and distal fingers, and
on amputation stumps.
Genital lesions occur primarily on the glans and prepuce
of the penis (19-21). The malignant nature of tumour may
easily be overlooked, particularly if the biopsy is small and
superficial. The squamous epithelium shows an asymmetric
exo and endophytic growth pattern with pushing margins.
Usually, there is deep penetration below the level of the
surrounding epidermis/mucosa. Tumour cells exhibit only
minimal atypia and very low mitotic activity. The presence
Siavash Rahimi
of neutrophils is an important diagnostic clue. No foci of
the usual squamous cell carcinoma should be found (22).
If the tumour is completely excised, prognosis is excel-
lent; after inadequate excision, the recurrence rate is high
and the survival decreases. In long-standing cases or after
irradiation and/or chemotherapy the biologic character of
the disease may change into a metastasizing squamous cell
carcinoma (23).
Adenosquamous carcinoma
Adenosquamous carcinoma is a rare variant of squamous
cell carcinoma arising from pluripotential cells related to
acrosyringia, characterized by the formation of mucin secre-
ting glands. The tumour consists of invasive tongues, sheets,
columns and strands of atypical dyskeratotic squamous cells,
merging with glandular structures with epithelial mucin
secretion. The tumour cells are positive for cytokeratin and
epithelial membrane antigen, whereas those cells forming
glands stain with CEA. There may be connection between
tumour cells and acrosyringia, as well as perineural invasion.
The tumours usually follow an aggressive course with the
capacity for metastasis and local recurrence.
Reporting of Squamous Cell Carcinomas
According to Royal College of Pathology the skin
SCC report should include clinical site, type of specimen
(excision), size of specimen (length, breadth, depth), maxi-
mum diameter of lesion, differentiation, Breslow thickness,
Clarke’s level, perineural invasion, vascular invasion. The
excision margins should describe the distance to nearest
peripheral margin and distance to nearest deep margin.
There are three tier systems for differentiation:
Modified Broder grading in line with recommendations
of the British Association of Dermatologists:
– Well differentiated: more than 75% of differentiated cells
(Broder grade 1);
– Moderately differentiated: more than 25% of differenti-
ated cells (Broder grade 2 and 3);
– Poorly differentiated: less than 25% of differentiated
cells (Broder grade 4).
Grading is done by averaging the whole tumour not by
the least differentiated area, although this might not be al-
ways consistent, in particular if there is an area with a very
aggressive appearance. If there is invasion in Bowen’s diseas
this is always a high grade carcinoma.
For practical managing purposes the tumours are divided
in low and high risk.
Low risk: well differentiated tumours less than 20 mm
in diameter arising in sun exposed areas excluding lip and
ear, less than 4 mm thickness and limited to the dermis in
individuals without immune dysfunction.
All other tumours are high risk.
Managing of tumours:
– High risk tumours require a resection margin of 6 mm.
– Low risk tumours require a resection margin of 4 mm
– The current practice is that the resection margins refer
to the peripheral margin.
Squamous Cell Carcinoma of Skin: A Brief Review
Molecular biology
p53
P53 is a tumor suppressor gene, the mutation of which
has been involved in the genesis of various cancers, including
SCC (24-29). When p53 is mutated it may lose its ability
to function normally in its role as a shepherd of the DNA
repair process or alternatively sending damaged cells into
programmed cell death (30-32). Overexpression of p53 pro-
tein in sun-damaged skin, AK, BD, and cutaneous SCC has
been reported in many studies (33-53). It has been shown that
mutant p53 accumulates in the cell nucleus, probably due
to increased half-life of the protein (5, 54). The presence of
p53 mutations in sun-exposed skin and premalignant lesions
suggests that p53 mutations arise early and may be required,
but not sufficient, for tumour development (55).
The finding that p53 mutations are present in AK and
in sun-damaged human skin suggests that p53 mutations
arise early during the development of SCC (46, 55, 56).
Furthermore, overexpression of p53 in the epidermis cor-
relates with sun exposure and sun damage, even in the ab-
sence of pre-malignant changes (51-53, 57). A few studies
attempted to determine a correlation between the level of
p53 expression and the morphological spectrum of the le-
sions developing on sun-damaged skin (40, 43, 46, 49). p53
was found to be already overexpressed in skin showing mild
solar elastosis and its expression was gradually increased to
a maximum level in advanced AK and SCC in situ. It was
also overexpressed in SCC that developed on sun exposed
areas, but to a lesser extent (58). Shimuzu et al. (40) graded
AK according to the amount of atypical cells within the
epidermis and found that the more atypical keratinocytes
present, the more p53 expression was detected. In their study,
both morphological grading and p53 expression correlated
with the proliferative activity as depicted by MIB-1 stain-
ing. Verdolini et al. (43) reported on a gradation of MIB-1
positivity and p53 expression with increasing abnormality
in the spectrum of keratinocytic malignancies of the skin
(AK, BD, microinvasive and invasive SCC). Barzilai et al.
(58) showed that with regard to p53, two groups of lesions
exist: one with low level of expression of p53 which includes
normal and sun-damaged skin, as well as SCC occurring on
sun-protected areas, and another group, which consists of
lesions with a high level of expression of p53, that includes
various ranges of AK and SCC developed on sun-damaged
skin. This latter finding is consistent with the perspective that
AK is a type of SCC (5, 59). This finding of an increased
p53 protein, either wild-type or mutant, in SCCs develop-
ing on sun-damaged skin is in accordance with cumulative
UVR effects on p53 protein expression. These cumulative
effects probably do not play a role in the development of
SCCs on sun-protected areas resulting in a lower level of
p53 expression. This relation between p53 expression in
SCC and sun exposure is also supported by the study of
Coulter et al (60) who found that p53 was overexpressed
in SCCs from sun-exposed skin in comparison to SCCs
arising on mucosal sites. This theme is further supported
by studies that have demonstrated identical p53 mutations
and nearly identical patterns of chromosomal aberrations in
145
AK and SCC (61-63). The incidence of p53-positive SCCs
and AKs varies greatly among the different studies (33-38,
40-43, 45-48, 53). With the range of 15% to 100% for SCC
and zero to 100% for AK. This great variability may be
accounted for by some reasons: many clones of antibodies
were used in the different studies and, although all of them
detect both the wild-type and the mutant p53 proteins, they
may have different sensitivities and different investigators
used different methods to evaluate the p53 expression, and
defined different threshold for considering expression as
positive. Furthermore, the degree of differentiation of SCC,
although with some contradictory results (34, 37, 41, 51) and
the histological type of AK (35, 36, 38) were also related
to p53 expression.
However, another factor which may explain this variance
of p53 expression in SCCs, and has biologic importance,
would be the relation between p53 expression and sun
exposure. Only two of the studies addressed this issue (37,
41) and both of them did not reveal a significant difference
in p53 expression between SCCs occurring on sun-damaged
skin and those developing on sun-protected areas.
CDKN2A
The CDKN2A locus on human chromosome 9p21 en-
codes two proteins named p16INK4a and p14ARF, known to
function as tumour suppressors via the retinoblastoma (Rb)
or the p53 pathway. Disruption of the p53 and Rb pathways
is a fundamental trend of most human cancer cells. Muta-
tions in the p53 gene and loss of expression of CDKN2A
via deletion play an important role in the pathogenesis of
SCC. While p53 mutations are induced by UVR, deletions
in CDKN2A could arise spontaneously, perhaps during
tumour progression. There are evidences that the develop-
ment of SCC on sun-damaged skin is a gradual process not
only morphologically but also on the molecular level. The
process starts already in normal-appearing epidermis with
SE. In that respect, AK should be regarded as a part of the
continuum in the development of SCC, analogous to the
situation in other epithelia. The molecular events involved
in the development of SCC on sun-exposed areas may be
different from those involving the development of SCC on
sun-protected areas (58).
Genetic alterations at the CDKN2A locus occur fre-
quently in a variety of human cancers (66).
Its involvement in SCC is not completely understood yet,
except for the studies conducted by Soufir et al. and Brown
et al. that showed inactivation of CDKN2A in 24% and 47%
of SCCs, respectively (65, 66). Some studies have shown
that SCCs harbour point mutations in the CDKN2A gene
at a low frequency (67) because inactivation of CDKN2A
can occur via deletion (68).
The biological consequences of genetic defects in the
CDKN2A locus in SCC are still not completely understood.
Because p14ARF protein seems to play a crucial role in
both the Rb and the p53 pathways independently as well as
through its interaction with E2F-1, it may be possible that
p14ARF and p53 have interdependent roles and that loss
of p14ARF expression is functionally equivalent to a p53
alteration (69).
146
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148 Siavash Rahimi