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 May/June 2014 Volume 12 • Issue 3

Core curriculum
Virendra N. Sehgal, MD, Section Editor

Basal Cell Carcinoma: Pathophysiology

Virendra N. Sehgal, MD;1 Kingshuk Chatterjee, DNB;1 Deepika Pandhi, MD;2 Ananta Khurana, MD2

Basal cell carcinoma (BCC) is the most common skin cancer in humans, which typically appears over the sun-exposed skin as a slow-
growing, locally invasive lesion that rarely metastasizes. Although the exact etiology of BCC is unknown, there exists a well-established
relationship between BCC and the pilo-sebaceous unit, and it is currently thought to originate from pluri-potential cells in the basal layer
of the epidermis or the follicle. The patched/hedgehog intracellular signaling pathway plays a central role in both sporadic BCCs and ne-
void BCC syndrome (Gorlin syndrome). This pathway is vital for the regulation of cell growth, and differentiation and loss of inhibition of
this pathway is associated with development of BCC. The sonic hedgehog protein is the most relevant to BCC; nevertheless, the Patched
(PTCH) protein is the ligand-binding component of the hedgehog receptor complex in the cell membrane. The other protein member of
the receptor complex, smoothened (SMO), is responsible for transducing hedgehog signaling to downstream genes, leading to abnormal
cell proliferation. The importance of this pathway is highlighted by the successful use in advanced forms of BCC of vismodegib, a Food and
Drug Administration-approved drug, that selectively inhibits SMO. The UV-specific nucleotide changes in the tumor suppressor genes,
TP53 and PTCH, have also been implicated in the development of BCC. (SKINmed. 2014;12:176–181)

C
utaneous malignancies may arise either from keratinocytes
or adnexal structures. Hair follicles and eccrine, apocrine,
and sebaceous glands are its usual sites. They may arise from
multiple origins. Skin cancers have been broadly divided into mela-
noma and nonmelanoma skin cancer (NMSC). NMSC consists of
squamous cell carcinoma and basal cell carcinoma (BCC). Among
them, BCC accounts for 75% to 90% of skin cancers and has
been regarded as the most common human malignancy.1,2 “Ulcus
rodens/Jakob”3 was coined for the first time for the entity known
as BCC today. “Carcinoma epitheliale adenoides”4 was described in
1900 to define BCC as a malignant, locally invasive, and destruc-
tive cancer. Three years after, the term “Basalzellenkrebs”5 was devel-
oped, proposing a classification of skin tumors, using histo-genetic
principles, emphasizing that the tumor originated in the basal layer
of the epidermis or hair follicle; thereafter, many workers6 have pro-
posed different names for the tumor, and the controversy prevails
regarding the cellular origin of BCC due to its locally aggressive but
overall benign course and rare tendency to metastasize. This has also
triggered a debate of whether BCC is truly a malignant tumor or
just a “semi-malignant tumor;” nevertheless, the World Health Or-
ganization’s7 classification has retained the term BCC. Significant
scientific research has been performed since 1974 to focus on the
ultrastructural, biochemical, genetic, molecular, and immunologic
undertones to define their role. Accordingly, several mysteries sur-
rounding BCC have been resolved, while a few remain. BCC affects
men more commonly than women.
Risk Factors
The most significant risk factor for BCC to develop appears to
be exposure to UV radiation.8 Early exposure during childhood
and adolescence is associated with a significant increase in risk of
the disease. In general, all NMSCs are more common in persons
with fair skin, blond/red hair, and light eye color and those who
have Fitzpatrick9 skin types I and II. Apart from that, cumulative
occupational exposure for an individual during their lifetime is
another important variable that has been recognized in BCC;
however, sufficient data with substantial conclusions are lacking
in order to incriminate occupational UV exposure in the devel-
opment of the disease. This subject must continue to be further
researched.10

From the Dermato-Venereology (Skin/VD) Center, Sehgal Nursing Home, Panchwati, and the Department of Dermatology
Bankura Sammilani Medical College West Bengal;1 and the Department of Dermatology and STD, University College of
Medical Sciences, and Associated Guru Teg Bahadur Hospital, Shahdara,2 Delhi, India
Address for Correspondence: Virendra N. Sehgal, MD, DermatoVenerology (Skin/VD) Center, Sehgal Nursing Home, A/6
Panchwati, Delhi-110 033, India • E-mail: drsehgal@ndf.vsnl.net.in

SKINmed. 2014;12:176–181 176 © 2014 Pulse Marketing & Communications, LLC

 May/June 2014 CORE CURRICULUM

According to the available epidemiologic data, predilection for Table I. Basal Cell Carcinoma: Risk Factors
BCC has been noted in childhood, in the age group of 0 to
UV radiation
19 years, in individuals with a history of intense exposure to
UV radiation. Lesions most commonly occur on a background Ionizing radiation13
of chronic photo-damaged skin. They are typically located over Immunosuppression drugs,14 renal transplantation15
the head and neck region.8 The presence of large numbers of Arsenic16
nevi, freckles, and solar elastosis are the other predisposing risk Psoralen and UV-A radiation17
factor(s); however, a history of acne is protective11,12 (Table I). Genodermatoses

Predisposing Genodermatoses

The presence of single/multiple BCC in the absence of any

predisposing factor(s), manifesting early in life, should arouse
doubt in the clinician about the possibility of heritable disor-
ders. These disorders18 are classified into 3 well-known groups,
with oculo-cutaneous albinism19 as another addition (Table II).
Pathophysiology
Genodermatoses studies have led to major breakthroughs in the
understanding of molecular changes that are now being mooted
towards the formation of BCC. During the past 80 years, different
hypotheses have been proposed to explain the nature and origin
of cells of BCC. Histopathologic variability of this tumor has not
been in consonance with derivation from any individual epithe-
lial structure. This tumor is generally considered to originate from
pluri-potent cells of epidermis, which may explain the propensity
of the tumor to differentiate to any of the epithelial structures, un-
der the control of signaling pathways20 and genetic constitution.21
The relevance of recent numerous studies, focusing on the new-
er insights into the pathogenesis of BCC should be taken into
perspective. Embryologically, both the bulge and hair matrix re-
gions of the fetal hair follicle are a rich source for stem cells, the
rapidly proliferating cells, more so with their abilities to facilitate
molecular signaling between the mesenchymal dermal papillae
and the developing hair follicle. This physiologic conversion22
has been found critical in the histo-genesis of BCC. BCC has
positively been associated with human leukocyte antigen-DR1
(HLA-DR1) and human leukocyte antigen-DR7 (HLA-DR7),
in the immunocompetent population, but substantial evidence
is lacking.23 Numerous studies24,25 on the Goltz-Gorlin syndrome
or the nevoid BCC syndrome (NBCCS) have emphasized on the
role of the hedgehog (Hh) signaling pathway, resulting from a
germline mutation of the Patched (PTCH) gene on the chromo-
some 9q26–3q27, coding a receptor for the Hh pathway.

Table II. Basal Cell Carcinoma: Predisposing Genodermatoses

Genetic Syndromes With BCC as a Genetic Syndromes With BCC as an Syndromes With Dubious Association
Prominent Feature Ancillary Feature With BCC
Bloom syndrome
Gorlin syndrome Sturge–Weber syndrome
Werner syndrome
Bazex–Dupré–Christol syndrome Klippel–Trenaunay syndrome
Rothmund–Thomson syndrome
Rombo syndrome Wyburn–Mason syndrome
Cowden syndrome
Generalized follicular basaloid hamartoma
syndrome
Schöpf–Schulz–Passarge syndrome
Happle-Tinschert syndrome
Epidermodysplasia verruciformis

Oculo-cutaneous albinism Fitzpatrick9 skin

type I and II, IV, V, and VI

Hermansky-Pudlak syndrome
Abbreviation: BCC, basal cell carcinoma.

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 May/June 2014 CORE CURRICULUM

Recently, PTCH mutations have been identified in sporadic

BCCs as well.28 The Hh family consists of a large number of
intercellular signaling proteins that play an essential role in pat-
terning invertebrate as well as vertebrate embryos.29 This family
of proteins owes its name to the appearance of the mutant fruit
fly, with abnormal proteins, simulating a curled-up hedgehog.
They were identified, at first, to regulate the segment polarity
and tissue organization in Drosophila melanogaster (fruit fly).30
It is now well-established that the Hh pathway has a significant
role in human development and cutaneous carcinogenesis. Con-
trary to fruit flies, vertebrates have evolved 3 different types of
homologs for the Hh gene, including the sonic, desert and In-
dian types. The differences in these 3 types of genes lie in their
patterns of expression in different animals. The Hh protein of
the vertebrate sonic-type gene (SHH) has two terminals. The C-
terminal peptide diffuses from the cell, whereas the N-terminal Figure. The hedgehog (Hh) signaling pathway.
is associated with the cell surface. PTCH is a membrane receptor
that acts as a human tumor suppressor protein. Binding of SHH
to PTCH is paramount in activating signals that regulate growth
degradation pathway via the SPOP complex. A fraction of the
and patterning embryos.31
Gli2/3 protein is processed into a repressor form, Gli-R, which
Another important component of the SHH pathway is a trans- inhibits Hh target gene transcription. Whereas the activated
membrane protein called smoothened (SMO). It is inhibited by (second) Hh ligand binding to PTCH-1 abrogates its inhibitory
PTCH, in the absence of Hh, blocking the expression of the effect on SMO, allowing SMO to translocate into the primary
target genes. This inhibitory effect of PTCH is nullified by the cilium and induce accumulation of the Gli-Sufu complex at the
binding of Hh to PTCH. Two types of PTCH genes have been tip of the primary cilium. Activation of the Hh pathway results
implicated in carcinogenesis. PTCH-1 is crucial for embryonic in accumulation of Gli-A and initiation of the transcription of
development, and its germline inactivation has been linked to Hh target genes such as PTCH1, GLI1, and HHIP 3.
the development of BCC. For BCC, rather than acting on an
Germline mutation of one PTCH-1 gene is seen in NBCCS.
individual basis, the PTCH-2 modulates carcinogenesis in as-
Mutations of both the alleles are required. PTCH-1 mutations
sociation with PTCH-1 haploinsufficiency.32,33
have been identified in 30% to 40% of sporadic BCCs.36,37 Re-
The hedgehog interacting protein (HIP) has recently been iden- cently, mutation of the PTCH-2 gene localized on chromosome
tified as a novel component of the vertebrate signaling pathway. 1p32.1–32.3 has also been identified in a case of sporadic BCC.38
It seems to encode a membrane glycoprotein that binds to the Studies have shown consistent overexpression of the PTCH-1
SHH protein with an affinity comparable to that of PTCH-1. mRNA in sporadic BCC by RT-PCR and in situ hybridization
There are other components of this complex signaling pathway. methods. PTCH-2 levels are high not only in BCC but also in
A simplified model has been described34 (Figure 1), according to normal epidermis.39 Mutation of SMO has also been identified
which PTCH-1 mutation may lead to aberrant activation of the in sporadic BCC.40 Several reports41,42 have highlighted an in-
SHH pathway, with increased target gene activation; however, crease in Gli-1 mRNA correlating with the overexpression of
the precise mechanisms leading to abnormal cell proliferation PTCH mRNA, as well as Gli-1 protein levels, in sporadic BCC
and differentiation have not yet been elucidated.35 Nevertheless, and in the basal layer of epidermis in the tumorigenic regions.
it is worthwhile to take stock of the plausible sequence of events Unchanged expression of Gli-2 mRNA in sporadic BCC and
that activate the pathway to comprehend its intricacies. unequivocal expression of Gli-3 mRNA levels in normal epider-
mis and sporadic BCC have also been observed.
Two components, namely off-state (first) and activated (second),
seem to play a significant role. The former (first) PTCH-1 re- Activation of SHH target genes expression, including HIP and
presses SMO activity. Gli2 and Gli3, the effectors of the Hh Wnt, has also been observed in sporadic BCC.43,44 Thus, both
pathway, are phosphorylated by a kinase cascade, which includes PTCH and SMO mutations can trigger overactivation of the
PKA, CK1, and GSK3β. They are directed to the proteasomal SHH pathway and result in the increased expression of the

SKINmed. 2014;12:176–181 178 Basal Cell Carcinoma: Pathophysiology

 May/June 2014
downstream target genes via the Gli family of transcriptional
factors. Gli-1 activates platelet-derived growth factor receptor-α
polypeptide (PDGFRA), which, in turn, upregulates the RAS-
MAPK1/RAS-ERK pathway. Activation of the RAS-MAPK1
pathway causes cell proliferation by inhibiting apoptosis. In-
creased expression of PDGFRA has been observed in mouse and
human models and may be important in BCC pathogenesis.45
Forkhead box (FOX) proteins have also been incriminated in the
physiopathology of BCC. These proteins regulate cell prolifera-
tion, growth, differentiation, longevity, and transformation. The
FOXE1 transcription factor is likely a direct downstream target
gene of Gli-2. FOX E1 has been documented to be expressed in
human basal keratinocytes and BCC. Also, the 1B isoform of
the FOXM1 gene is upregulated in BCC.46 Cadherin-associated
protein, beta 1 (CTNNB1), also known as b-catenin, is a nu-
clear effector of WNT and a downstream mediator of the SHH
pathway. CTNNB1 activity increases transcription of genes
involved in tumor formation. Among these genes are MYCN
and cyclin D1, which contribute to cellular proliferation and
matrix meta-llopeptidase 7 (MMP 7), whose gene product may
facilitate stromal invasion by tumors. In BCC, however, wheth-
er SHH pathway misregulation, WNT pathway upregulation,
nuclear CTNNB1 accumulation, and cellular proliferation are
mechanistically linked remains a matter of dispute.47,48
Aberrant SHH signaling may also lead to BCC expressing in-
creased levels of antiapoptotic proto-oncogene, BCL2 (B-cell
CLL/lymphoma 2). BCL2 is expressed in the basal cell layer of
the epidermis and a 2- to 3-fold increase is seen in BCCs. Al-
though a link between SHH misregulation and BCL2 has been
suggested, results on BCL2 gene expression in BCCs have been
inconsistent.49 The N-myc proto-oncogene (MYCN) is a mem-
ber of the Myc family of transcriptional activators and a poten-
tial downstream effector of the SHH pathway. MYCN upregula-
tion has been associated with BCC. Immunohistochemistry and
fluorescence in situ hybridization has depicted increased MYCN
production in 73% of 220 BCCs. Aggressive infiltrative BCCs
have higher MYCN gene expression than nodular and superficial
BCCs.50 RUXN3, a member of the runt-related transcription
factor (RUNX) gene family, is a tumor suppressor gene. It is nor-
mally expressed in the basal layers of the epidermis. Researchers51
demonstrated that the RUNX3 gene is overexpressed in BCCs,
compared with expression in normal epidermis. The Hh path-
way is an important regulator of embryologic development and
is also involved in carcinogenesis. A proper understanding of this
signaling pathway, its aberrant activation and associated molecu-
lar components, seems pertinent in the perspective of emerging
targeted therapeutic modalities.
SKINmed. 2014;12:176–181 179
CORE CURRICULUM
The connection between BCC pathogenesis and misregulation
of the SHH pathway due to inactivating PTCH1 mutations and
activating SMO mutations is well-documented. Upregulation
of Hh signaling is the pivotal abnormality in BCC.47 Approxi-
mately 90% of sporadic BCCs have loss of function in at least
one allele of PTCH-1 and 10% have activating mutations of the
downstream SMO protein.48,49,50 The loss-of-function mutation
of the PTCH-1 includes germline mutations found in the Gor-
lin syndrome. With these mutations and dysregulations of the
Hh pathway, SMO is active, resulting in continuous target gene
activation. The expression of mRNAs from these target genes is
increased in BCCs. Mutations of the p53 tumor suppressor gene
has been documented in 50% of cases of sporadic BCC.51
Conclusions
BCC is the most frequently encountered human malignancy.
It seems to emanate from the epidermis, the precise origin of
which is still unknown and thus not clearly elucidated. The un-
derlying pathophysiology of this tumor includes an interaction
among various proteins involved in cellular proliferation and dif-
ferentiation. The Hg and PTCH pathways seem to be the clues
to help understand the pathophysiology of this malignancy, for
which further research is needed.
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Historical Diagnosis and treatment

Diagnosis and treatments have advanced over the past century. This feature depicts
conditions from a collection of stereoscopic cards published in 1910 by The Stereoscopic
Skin Clinic by, Dr S. I. Rainforth.

(Continued on page 189)

SKINmed. 2014;12:176–181 181 Basal Cell Carcinoma: Pathophysiology

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