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Page 12 of 40 Maner et al. J Cancer Metastasis Treat 2020;6:37 I http://dx.doi.org/10.20517/2394-4722.2020.60

10% of AKs progress to cSCC. In one school of thought, the fate of AK is dependent a stepwise progression
through several stages, driven by complex immunologic mechanisms. In many cases, AKs may present
asymptomatically with little or no inflammation. These lesions may be subclassified as asymptomatic
actinic keratoses (AAK). Although initially asymptomatic, some AKs become inflamed and present
symptomatically and thus may be classified as inflamed actinic keratoses (IAKs).

It is thought that some AAKs progress to IAKs as cells undergo molecular and immunologic changes that
promote increased growth and inflammation. For example, Fas ligand (FasL) site desensitization may lead
+
+
to the inhibition of CD8 T lymphocytes resulting in impaired CD8 -mediated apoptosis and thus promote
[76]
lesion progression . Other AAKs may not undergo the changes necessary for progression and remain
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+
+
asymptomatic. It has also been shown that IAKs recruit immune cells, including CD3 , CD4 , CD8 T
[84]
lymphocytes, and Langerhans cells, producing further inflammation . Should an IAK experience sufficient
growth and keratinocyte damage, it may progress to cSCC in situ or Bowen’s Disease. Bowen’s Disease is
slow-growing and shows displays only partial-thickness atypia. With further inflammation, damage, and
mutations of keratinocytes, Bowen’s disease can evolve into cSCC with full thickness atypia and potential
to invade and metastasize. The role of inflammation in the progression from AAK to IAK to cSCC is also
supported by a stepwise increase in the expression of Bcl-2. Overall, the UV damage of keratinocyte DNA
leads to the progression of a pre-cancerous asymptomatic lesion into a malignancy.

Secondary to UV induced cSCC are those induced through keratinocyte signaling mutation induced by
chronic inflammation. Injury to the skin causes a wound healing cascade to occur, activating keratinocyte
proliferation and many of the cell signaling pathways that are involved in tumorigenesis. The EGFR
pathway, the intrinsic pathway, and the extrinsic inflammatory pathways are all included in the cell
signaling pathways causing tumorigenesis. Chronic inflammatory conditions, including lichen sclerosus,
may activate the intrinsic pathways causing chronic inflammation, increased cell turn over, and possible
[85]
tumorigenesis by activating wound healing and repair simultaneously . The extrinsic pathway includes
the influence of environmental factors and viral causes of inflammation, including human papillomavirus
(HPV) [Figure 7]. The viral mechanisms of HPV will be discussed later in the verrucous carcinoma
[85]
section. This pathway involves the release of a cascade of inflammatory cytokines and chemokines which
promote the migration of lymphocytes to the injury site and subsequent repair. Chemokines can enhance
cell turnover causing increased DNA replication, predisposing cells to genetic mutations that foster the
formation of tumors such as cSCC. In addition, cutaneous unilateral linear porokeratosis, another chronic
inflammatory disease, has high potential for malignant transformation due to its mutations in psoriasin,
p16 INK4a , and involucrin, similar to that of cSCC but at a lower level . However, when the AKs and cSCC
[87]
lesions do appear, they produce chemokines that increase metastatic potential.

Chemically induced mutagenesis
Cell growth and apoptosis
Chemicals, including arsenic and pharmacologic agents, may be implicated in the development of cSCCs.
Chronic exposure to high concentrations of arsenic in food and drinking water is a common cause of
cSCC, especially cSCC on the palms. Arsenic levels in drinking water as low as 300 μg/L have been
[88]
found to cause cSCC . Levels between 200-1000 μg/L have been identified in 2013 in the ground water
[89]
in multiple communities in Massachusetts . There are many medications and vaccinations that include
the use of arsenic as adjuvants, active and inactive ingredients depending on the medication or vaccine;
however, the amount within these pharmacologic agents is not enough to evoke malignant transformation
of keratinocytes. Nonetheless, there is a need for further research on the chronic exposure of small amounts
of arsenic and possible malignancies. Arsenic-exposed hyperkeratotic epithelial cells express elevated levels
of keratin-1, keratin-10, involucrin, and loricrin, biochemical mediators important to the proliferation of
[88]
keratinocytes . These lesions can further progress to become Bowen’s disease and later cSCC with full