Page 469 - Read Online

Maner et al. J Cancer Metastasis Treat 2020;6:37 I http://dx.doi.org/10.20517/2394-4722.2020.60 Page 21 of 40

BCC and SCC suggest that strong FasL expression plays a role in allowing BSC to avoid apoptosis. BSC that
do not have strong expression of FasL may not be able to avoid apoptosis or may avoid apoptosis through
other means.

Additionally, bcl-2 promotes cell survival without stimulating cell proliferation. Bcl-2 is associated with
the intrinsic apoptotic pathway, triggered by intracellular stress [140] . Studies indicate that bcl-2 positive
tumors have a better prognosis and slower course of progression. In BSC, immunohistochemical studies
for bcl-2 yield a positive result in the BCC regions but a negative result in both the transition zone and
SCC region [141] . Studies show only low-grade bcl-2 positivity in the BCC regions of BSC, similar to that of
aggressive BCC. In contrast, non-aggressive BCC such as nodular and superficial BCC have high grade bcl-2
positivity. This suggests that BSC may downregulate bcl-2 in the BCC regions, stimulating uncontrolled cell
proliferation and contributing to its more aggressive behavior compared to non-aggressive BCC [141] .

Crosstalk
Crosstalk between various signaling pathways can be a determining factor as to why some patients respond
to cancer treatments and others fail treatments. In fact, the BSC pathways and hair follicle pathways appear
to have significant crosstalk; both of these pathways are dependent on SHH, PTCH1, SMO, and Gli [142] . In
normal hair follicle development, PTCH1 acts as a receptor for SHH, and their interaction triggers SMO
which modulates a signaling cascade. Activation of the SMO cascade results in subsequent translocation
of Gli to the nucleus. Gli is a key modulator of the SHH pathway and causes upregulation of several
downstream target genes that modulate hair follicle development [143] . Injury to skin enlists hair follicle
stem cells in the healing process, namely through the SHH pathway. However, if cells that carry a mutation
in SMO are recruited to the injury site, this mutation will trigger unregulated downstream SHH pathway
signaling which is implicated in BCC and BSC [144] . This shared SHH pathway involvement suggests that
the mechanisms of tumor formation and hair follicle proliferation are interlinked and essential for the
normal development of hair follicles with dysregulation or mutation in this pathway leading to cancer [143] .
It is possible that BSC originates as BCC from pluripotent basal cells and initiates in a similar manner as
BCC, typically from hair follicle stem cells in the hair follicle bulge [145] , as seen in the previous BCC section.
Through modulating pathways conferring plasticity as described above, squamatization occurs to form
BSC.

Vismodegib is a SHH pathway inhibitor that is used for the treatment of BCC. There have been many cases
of SCC developing from BCC following treatment with Vismodegib. The appearance of SCC may indicate
a de novo SCC adjacent to the BCC which is proliferating independently, an SCC that develops as a result
of stem cell differentiation during SHH inhibition, or an SCC that was present as part of a metatypical
BCC such as BSC that has decreased SHH signaling due to SHH inhibition and subsequently increased
RAS/MAPK signaling [146] . There fails to be many reported cases of SCC transforming to BCC following
use of Vismodegib. Thus, it may be difficult to determine if SHH inhibitors could play a role in the
desquamatization of cSCC to BCC. Nevertheless, because BSC has a high tendency for recurrence and has
a high rate of metastasis, Moh’s micrographic surgery is currently the preferred treatment for BSC [128] .

Supporting stroma and vascularization
When comparing supporting stroma of BCC and BSC, there is a significant difference between the stroma
of BSC, and high risk (HR) BCCs (micronodular and/or infiltrative) compared to that of low risk (LR)
BCCs (nodular and/or superficial). LR BCC group lesions have fibromyxoid stroma without desmoplastic
stroma, whereas 80% of the HR BCC and 61.8% of the BSC group lesions have desmoplastic stroma [147] .

The stromal differences in LR and HR BCCs and BSC further suggests variety between the tumor types.
Fibromyxoid stroma is most often observed in lesions with mild inflammation. However, desmoplastic