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23 Neoplasia: Basic Concepts
410
● The term ‘malignant’ refers to a locally invasive tumour that can spread to distant places.
Malignant tumours are collectively called cancers, which stem from the Latin word for ‘crab’
because they infiltrate and seize on normal tissues tenaciously, similar to how a crab does. Not
all cancers are aggressive, and some of the most aggressive are also highly treatable, but the term
‘malignant’ sends a warning signal.
All tumours, whether benign or malignant, have two basic components: (i) parenchyma, which
is composed of aberrant or neoplastic cells and (ii) stroma, which is made up of host- derived, nonneoplastic connective tissue, inflammatory cells and blood vessels(2, 3).
23.3 Benign Tumours
Generally, benign tumours are identified by adding the suffix - oma to the cell type from which the
tumour originated. A benign fibroblast tumour, for example, is a fibroma, whereas a benign cartilaginous tumour is a chondroma. Exceptions to this rule include melanoma and lymphoma, which
are malignant neoplasms. Benign epithelial tumours are classified using more complicated terminology(3). Below are examples of the most known benign tumours in the oral cavity.
Adenoma: Benign neoplasm derived from glandular cells.
Papilloma: Benign epithelial overgrowth showing finger- like projections supported by a delicate
connective tissue core.
Polyp is a general term for an exophytic or sessile overgrowth separate from the skin or mucosa
that could be neoplastic or inflammatory.
23.4 Malignant Tumours
With some modifications and exclusions, the nomenclature of malignant tumours mostly corresponds to that of benign tumours. The terminology used to describe neoplasms is complicated and
occasionally inconsistent. Yet, students need to understand since it helps doctors communicate the
type and importance of a tumour(2). Below are several terms used to describe groups of malignant
neoplasms(2).
Carcinomas are malignant neoplasms of epithelial cells that could originate from ectoderm
(e.g. skin or salivary glands), mesoderm (e.g. renal tubular epithelium) or endoderm (e.g. lining
epithelium of the stomach). Some carcinomas could be subclassified based on their differentiation,
which is the process by which cells, tissues and organs acquire specialised features. Carcinomas
that exhibit minimal or no differentiation are known as poorly differentiated or undifferentiated
tumours(2, 4). Oral squamous cell carcinoma (OSCC) is the most common malignant tumour in
the head and neck region and is characterised by a complex carcinogenesis process(5).
Sarcomas are malignant solid neoplasms of mesenchymal cells, while lymphoma or leukaemia
are malignant neoplasms derived from blood cells(3).
Melanomas are malignant neoplasms derived from melanocytes(3).
Germ cell tumours are malignant neoplasms derived from germ cells(3).
Microscopically, neoplastic cells of either malignant or benign tumours share morphological
characteristics with one another, indicating that they may originate from a single altered
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Figure23.1 Photomicrograph of pleomorphic adenoma of minor salivary gland. Pale epithelial cells
devoid of any cytological atypia are seen. There are little ducts in certain places, some of which contain
what seems to be mucous eosinophilic material. The stroma in which the cells are located is mainly
hyalinised but also occasionally myxoid.
progenitor cell(6, 7). In a few exceptional cases, the tumour cells differentiate differently, resulting
in what are known as ‘mixed tumours’ (3). Although progenitor cells in mixed neoplasms can
develop along many lineages, the tumours themselves are clonal. A typical instance is a pleomorphic adenoma of the salivary gland. This benign tumour contains scattered epithelial components
within a fibromyxoid stroma, occasionally containing islands of bone or cartilage (Figure23.1).
Another example of a mixed tumour is teratoma, which comprises identifiable immature or
mature cells or tissues from two or all three germ cell layers. Teratomas stem from totipotent germ
cells, found in midline embryonic resting and often in the ovary and testis(2). Because germ cells
may develop into every type of cell seen in an adult organism, they can cause neoplasms that
include components that resemble bone, muscle, fat, nerve and other tissues combined unevenly.
Interestingly, some tumour nomenclature may cause some confusion. A few malignant neoplasms, for instance, are referred to by the words lymphoma, mesothelioma, melanoma and seminoma(2). On the other hand, some lesions are insignificant, but because of the term ‘oma’, which
implies a tumour in their name, it gives them an unwarranted gravitas. Typical examples are
hamartoma and choristoma. A hamartoma is a mass of jumbled tissue that resembles the organ
involved, such as the liver or lungs. Though hamartomas were formerly assumed to be developmental abnormalities, they are better described as atypical benign neoplasms due to clonal chromosomal aberrations acquired by somatic mutations(2, 8). Several oral hamartomas appeared as
congenital epulis(8). Meanwhile, choristoma is ‘a tumour- like mass of normal cells in an abnormal location’(9). Choristoma is rare in the oral cavity and primarily seen in the tongue(9).
411
23.5 Features ofBenign andMalignant Neoplasms
Anaplasia, local invasion and metastasis are the main features distinguishing benign tumours
from malignant neoplasms. Rapid growth indicates malignancy; however, the growth rate is not a
good discriminator because malignant tumours can grow slowly. While many tumours are challenging to characterise, most neoplasms may be classified as benign or malignant with remarkable
accuracy by applying established standards(2, 4).
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23 Neoplasia: Basic Concepts
412
23.5.1 Anaplasia
Anaplasia is the absence of differentiation, whereas differentiation is the degree to which
neoplasms resemble their parent cells. Benign neoplasms often consist of well- differentiated cells
that closely resemble normal cells. Mature cartilage cells that differentiate morphologically and
functionally produce a cartilaginous matrix, constituting a chondroma. Mature fat cells loaded
with cytoplasmic lipid vacuoles make up a lipoma. Mitoses are often infrequent and have a normal
structure in well- differentiated benign tumours(2). Conversely, morphologic changes that indicate a neoplasm’s malignancy are present in most cases. Certain features of well- differentiated
tumours might be rather inconspicuous. Furthermore, malignancies may elicit stromal responses
that are absent in benign tumours(2). In this context, mentioning the term ‘dysplasia’ is noteworthy, which is disorderly proliferation(10). Chapter27 in this book discusses oral epithelial dysplasia in more significant detail. Oral epithelial dysplasia is frequently detected in a group of lesions
and conditions with a higher risk of malignant transformation, termed oral potentially malignant
disorders(11). The lack of individual cell homogeneity and distorted architectural orientation are
characteristics of dysplastic epithelium. Pleomorphism is a characteristic of dysplastic cells, which
frequently have massive, hyperchromatic nuclei. Abnormally numerous mitotic figures often
occur in the superficial epithelium(2).
Anaplastic cells frequently exhibit the following characteristics:
● Cellular and nuclear pleomorphism. Shape and size variations are seen in tumour cells and their
nuclei (Figure23.2). A dark staining known as hyperchromasia or abnormally prominent nucleoli, either solitary or numerous, are also visible in nuclei. As a result of nuclei enlargement, the
nuclear- to- cytoplasmic ratio may rise to almost 1:1, compared to the typical 1:4 or 1:6. Nucleoli
can grow to incredible proportions, occasionally getting close to the diameter of typical
lymphocytes(2).
● Atypical mitoses may occur in large numbers. Multiple spindles might result in tripolar or quad-
ripolar mitotic figures (Figure23.2)(2).
● Loss of polarity, in which cells develop in sheets, with loss of normal orientation and absence of
distinct growth patterns, such as glands or stratified squamous architecture(2).
Figure23.2 Atypical mitoses. Note the significant variations in cell and nucleus shape and size– many
cells have abnormally prominent nucleoli and abundant atypical mitoses in a poorly differentiated
squamous cell carcinoma.
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References
23.5.2 Local Invasion
Cancer development is followed by increasing infiltration, invasion and destruction of surrounding
tissues, whereas most benign tumours develop as cohesive expansile masses that stay confined(4).
Because benign tumours grow and spread slowly, they typically form a ring of compressed fibrous
tissue known as the capsule. The capsule comprises an extracellular matrix formed by stromal cells
such as fibroblasts, which can be triggered by mechanical stress caused by the developing tumour
compressing normal tissue. Encapsulation forms a tissue plane, making the tumour distinct, movable (nonfixed), and easily excised with surgical enucleation. Not all benign neoplasms are encapsulated(2, 4).
Invasiveness is the characteristic that most accurately separates malignancies from benign
tumours, second only to the appearance of metastases. Malignancies do not usually form capsules.
Hence, surgeons must carefully identify the invasive front of malignancies to ensure complete
resection and clearance of malignant cells(2, 4).
23.5.3 Metastasis
Malignant neoplasms are characterised by metastasis, which is the spread of a tumour to places
physically distinct from the original site. Cancers can spread because of their invasiveness, which
allows them to enter bodily cavities, lymphatic systems and blood arteries. In all, 20% of patients
with newly diagnosed solid tumours (apart from skin malignancies other than melanomas) have
occult metastases at the time of diagnosis, and around 30% of patients with newly diagnosed solid
tumours present with clinically apparent metastases(2, 4).
One of three mechanisms might cause malignant neoplasms to spread: (i) germination inside
bodily cavities, (ii) lymphatic dissemination or (iii) hematogenous dissemination(2). When neoplasms enter a bodily cavity, they spread by seeding. Carcinomas tend to spread more lymphatically, whereas sarcomas prefer hematogenous dissemination. Carcinomas of the oral cavity are
frequently metastasised to cervical lymph nodes(12).
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23.6 Summary
Evolution of neoplasms is a complex process. The nomenclature primarily depends on the tumour
cells’ morphology and origin. Anaplasia, local invasion and metastasis are the main features distinguishing benign tumours from malignant neoplasms.
References
1 Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, etal. Global cancer statistics
2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries.
CA Cancer J Clin. 2021;71(3):209– 49.
2 Kumar V, Abbas AK, Aster JC, Deyrup AT, Das A. Robbins & Kumar Basic Pathology, 11th edition.
Elsevier; 2023.
3 Prabhu SR. Neoplasia and carcinogenesis. In: Textbook of General Pathology for Dental Students.
Cham: Springer Nature Switzerland; 2023, pp. 81– 96.
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23 Neoplasia: Basic Concepts
414
4 Cooper GM. The Cell: A Molecular Approach, 2nd edition. Sunderland (MA): Sinauer
Associates; 2000.
5 Chitturi Suryaprakash RT, Shearston K, Farah CS, Fox SA, Iqbal MM, Kadolsky U, etal. A novel
preclinical invitro 3D model of oral carcinogenesis for biomarker discovery and drug testing. Int J
Mol Sci. 2023;24(4):4096.
6 Cao Y. Tumorigenesis as a process of gradual loss of original cell identity and gain of properties of
neural precursor/progenitor cells. Cell & Bioscience. 2017;7(1):61.
7 Farah CS, Shearston K, Nguyen AP, Kujan O. Oral carcinogenesis and malignant transformation.
In: Brennan PA, Aldridge T, Dwivedi RC, editors. Premalignant Conditions of the Oral Cavity.
Singapore: Springer Singapore; 2019, pp. 27– 66.
8 Kujan O, Clark S, Sloan P. Leiomyomatous hamartoma presenting as a congenital epulis. Br J Oral
Maxillofac Surg. 2007;45(3):228– 30.
9 Chou LS, Hansen LS, Daniels TE. Choristomas of the oral cavity: a review. Oral Surg Oral Med
Oral Pathol. 1991;72(5):584– 93.
10 Odell E, Kujan O, Warnakulasuriya S, Sloan P. Oral epithelial dysplasia: recognition, grading and
clinical significance. Oral Dis. 2021;27(8):1947– 76.
11 El- Sakka H, Kujan O, Farah CS. Assessing miRNAs profile expression as a risk stratification
biomarker in oral potentially malignant disorders: a systematic review. Oral Oncol. 2018;77:57– 82.
12 Napier S. Lip and oral cavity carcinomas. In: Boyle DP, Allen DC, editors. Histopathology Reporting:
Guidelines for Surgical Cancer. Cham: Springer International Publishing; 2020, pp. 149– 55.
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24
Molecular Basis ofCancer
Lalima Tiwari and Omar Kujan
UWA Dental School, The University of Western Australia, Perth, Western Australia, Australia
24.1 Introduction
The evolution of cancer biology over the last three decades has dramatically changed our
understanding of the molecular origins of cancer. Genomic technology now allows us to comprehensively understand molecular foundations of cancer- causing events starting from the conversion
of non- lethal cells responsive to homeostatic feedback mechanisms to cells capable of autonomous
growth and invasion. Simply speaking, cancer results from a series of genetic and epigenetic alterations causing a loss of normal growth controls, resulting in unregulated growth, lack of differentiation, apoptosis, genomic instability and metastasis. These processes have now been classified as the
hallmarks of cancer and are shared commonalities that unite all types of cancer cells at the level of
cellular phenotype(1, 2). Understanding how alterations of biological pathways can lead to carcinogenesis is crucial to developing novel cancer diagnosis and treatment strategies.
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24.2 Hallmarks ofCancer
The hallmarks of cancer were developed to describe the specific functional capabilities human
cells acquire as they make their way from normalcy to a neoplastic growth state during tumour
pathogenesis(2, 3). These principles were influenced by recognising that human cancers develop
as products of multistep processes. Currently, eight recognised hallmarks and two enabling characteristics of cancer are considered functional capabilities the cells acquire for neoplastic
growth(3). More recently, two more emerging hallmarks and enabling characteristics have been
added to the list based on increasing knowledge within this field (Figure24.1)(3).
Cancer hallmarks include:
1) Sustaining proliferative signalling
2) Evading growth suppressors
3) Resisting cell death
4) Enabling replicative immortality
5) Inducing/accessing vasculature
Pathological Basis of Oral and Maxillofacial Diseases, First Edition. Edited by S. R. Prabhu, Syed Ali Khurram,
Omar Kujan and Merva Soluk Tekkesin.
© 2025 John Wiley & Sons Ltd. Published 2025 by John Wiley & Sons Ltd.
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instability and
vasculature
and metastasis
416
proliferative signalling
Sustaining
Deregulating
cellular
metabolism
Resisting
cell death
Genome
mutation
Inducing or accessing
Evading
growth suppressors
Avoiding
immune
destruction
Tumour-promoting
inflammation
Activating invasion
Enabling
replicative
immortality
Unlocking
phenotypic
plasticity
Senescent
Figure24.1 Hallmarks of cancer. Source: Adapted from Hanahan(2).
6) Activating invasion and metastasis
7) Reprogramming cellular metabolism
8) Avoiding immune destruction
Enabling characteristics:
1) Genomic instability
2) Tumour- promoting inflammation
Emerging hallmarks and
enabling characteristics
cells
Non-mutational
epigenetic
reprogramming
Polymorphic
microbiomes
Emerging hallmarks and enabling characteristics:
1) Unlocking phenotypic plasticity
2) Senescent cells
3) Epigenetic reprogramming
4) Polymorphic microbiomes
24.3 Sustaining Proliferative Signalling
Proto- oncogenes are a group of genes that cause normal cells to become cancerous when they are
mutated(4). They are the first regulatory factors of the cancer biological process. Proto- oncogenes
normally function as growth factors, transducers of cellular signals and nuclear transcription factors (Table 24.1) (4). Their function is to control normal cell differentiation and proliferation.
Mutations to these genes can activate proto- oncogenes, influence their function and develop into
cancer cells, known as oncogenes. It is the oncogenic formation that drives and sustains cell proliferation. It is important to note that proliferation is vital in the formation of mutations and the
expansion of clones of cells bearing these mutations(2, 3). Currently, there are 50– 60 oncogenes
that have been recognised(4).
The genetic alterations that lead to the activation of proto- oncogenes and the development of
oncogenes include mechanisms associated with influencing the structure of the encoded protein
and those that cause deregulation of protein expression within the proto- oncogene(4).
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24.3 Sustaining Proliferative Signalling
Table24.1 Proto- oncogenes witha role inthe regulation ofcell growth signals.
417
Role in mitogen signal
transduction
Growth factor
Growth factors SIS Platelet- derived growth factor
Transduction factors
with kinase action
Nuclear transcription
factors
Anti- apoptotic factors BCL2 B- cell lymphoma two protein Inhibition of apoptosis
Binding to protein p53 MDM2 Mouse double minute 2 homolog Transcriptional regulation
Proto-
oncogene Encoded protein
ERBB Receptor tyrosine- protein kinase Cell membrane receptor for
ERBB2 Receptor tyrosine- protein kinase
ERBB2
FMS Tyrosine- protein kinase
transforming protein fms
MET Tyrosine- protein kinase Met Receptor for HGF
RET Receptor tyrosine kinase Receptor for GDNF
(PDGF)
HST Homogentisate
solanesyltransferase, chloroplastic
FGF5 Fibroblast growth factor 5 Growth factor for fibroblasts
ABL Tyrosine- protein kinase ABL Tyrosine kinase
SRC Tyrosine- protein kinase Src Tyrosine kinase
RAS RAS small GTPase G- Protein
SOS Guanine nucleotide exchange
factors
CDK4 Cyclin- dependent kinase four
protein
FOS Leucine zipper protein Transcription factor
JUN Activator protein 1 Transcription factor
MYC MYC transcription factor protein Transcription factor
GLI GLI family zinc finger 1 Transcription factor
TTG Tissue transglutaminase Transcription factor
ERBA Thyroid hormone receptor alpha Member of the steroid
Function of the proto-
oncogene product
interleukin
Growth factor receptor
Receptor for CSF1
β- Chain for PDGF
Growth factor for FGF
Exchange factor of
nucleotide of guanine
Cyclin- dependent kinase
receptor family
Note. EGF: Epidermal growth factors; CSF1: inducing factor of macrophage- 1 colonisation; HGF: hepatocyte
growth factor; FGF: fibroblast growth factor; GDNF: glial- derived necrotic factor.
Source: Adapted from(4).
These include:
1) Point mutations of a proto- oncogene, where substitution of a single base by another base is
translated by substituting an amino acid in the oncoprotein (e.g. RAS oncogene). These alterations often lead to uncontrolled, continuous activity of the mutated protein(4).
2) Chromosomal translocation of a proto- oncogene from a location that cannot be transcribed to
an adjacent location where it can be transcribed and produce fusion genes that relay
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418
proliferative signals, such as the Philadelphia translocation (BRC- ABL). Such mechanisms acti-
vate the fusion gene permanently, leading to unregulated cell cycling(4).
3) Amplification of genes by incorporating multiple copies of an oncogene, resulting in increased
production of an oncoprotein (e.g. c- MYC in neuroblastoma)(4).
4) Incorporation of a promoter gene near the proto- oncogene results in overexpression of the gene
(e.g. the retrovirus carcinogenicity mechanism)(4).
Oncogene products comprise a variety of molecules, such as transcription factors, growth factors, growth factor receptors, signal transducers and apoptosis regulators to sustain proliferative
signalling(2, 5– 7). These are referred to as oncoproteins and function similarly to their ‘normal’
protein counterparts, with the critical difference that they are usually always active and are autonomous from normal checkpoints, resulting in abnormal neoplastic growth. The most known
examples of proto- oncogenes include RAS, WNT, MYC, ERK and TRK(3).
24.4 Evading Growth Suppressors
Another hallmark of cancer is its ability to evade tumour suppressor genes’ actions(2, 3). Tumour
cells evade these genes by genetic mechanisms, including chromosomal deletion, mutation and
inactivation, or loss of upstream or downstream efforts and by epigenetic mechanisms, including
DNA methylation, histone methylation and acetylation(8). Tumour suppressor genes are still identified through their characteristic inactivation in cancer (Table24.2). The most common examples
of tumour suppressor genes include the retinoblastoma (Rb) gene and tumour protein 53 (TP53)(3).
The Rb gene was one of the first recognised tumour suppressor genes. It is integral in driving cellcycle progression by integrating signals from diverse extracellular and intracellular sources(8). It
permits a cell to proceed through its growth and division cycle. Mutations of the Rb pathway function lose these critical gatekeepers of the cell- cycle progression, resulting in persistent cell proliferation(8). Loss of p53leads to the loss of cell- cycle checkpoints, the ability of the cell to arrest and
effectively repair DNA errors or damage, and the accumulation of genetic instability and accumulation of mutations. Further, loss of P53leads to inappropriate survival of cells with new mutations, as it is also responsible for triggering apoptosis(8). Mutations and loss of p53 are prevalent in
cancers related to carcinogens in tobacco smoke, such as lung, head, neck and bladder cancer(8).
Mechanisms on how evasion of these tumour suppressor genes occurs are due to the loss, mutation and methylation of cyclin- dependent kinase inhibitor (CDKN) 2a locus on chromosome 9p21,
which leads to the loss of CDKN, p16ink4a and often the mouse double minute 2 homolog
(hMDM2) inhibitor p14ARF(8). The loss of p16ink4a results in the activation of CDK4/6, which
phosphorylates the Rb protein that activates E2F- mediated transcription of genes involved in entry
into the cell cycle, allowing cells to continue entering the cell- cycle pathway(8). Loss of p14ARF
protein also results in MDM2 activity and resultant degradation of p53(8). The dysfunctional pathways activated by the loss of tumour suppressors provide continuous, unopposed growth- promoting
signals. These pathways, however, have become potential targets for anti- cancer therapy and, for
example, have resulted in the development of CDK4/6 inhibitors that restore Rb function(8).
24.5 Resisting Cell Death
Apoptosis is a mode of programmed cell death essential to maintain tissue homeostasis by eliminating unwanted, damaged cells(10). Apoptosis is a discrete process comprising two primary pathways: intrinsic (mitochondrial) and extrinsic (death receptor) pathways. The deregulation of these
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Table24.2 Tumour suppressor genes andtheir associated function.
Gene Familial cancer syndrome Function
TP53 Li- Fraumeni syndrome Cell- cycle regulation, apoptosis
RB1 Familial retinoblastoma Cell- cycle regulation
P16(INK4a) Familial melanoma Cell- cycle regulation
P14(ARF) Familial melanoma MDM2 antagonist
CHK ½ Li- Fraumeni syndrome Protein kinase (G1 control)
KLF6 Unknown Transcriptional regulation
NF1 Neurofibromatosis type I Catalysis of RAS inactivation
APC Familial adenomatous polyposis Inhibition of signal transduction
TSC1 Tuberous sclerosis 1 Interaction with tuberculin
DCC Deleted in colorectal carcinoma Transmembrane receptor
BRCA1 Familial breast cancer Cell cycle, DNA repair
MSH2 Hereditary non- polyposis colorectal cancer DNA mismatch repair
MLH1 Hereditary non- polyposis colorectal cancer DNA mismatch repair
PTEN Cowden syndrome P1- 3kinase signal transduction
LKB1 Peutz– Jeghers syndrome Phosphorylation and activation of AMPK
CDH1 Familial diffuse gastric cancer Cell– cell adhesion protein
TGF- R I Unknown Growth inhibition
TGFR II Unknown Growth inhibition
SMAD4 Familial juvenile polyposis syndrome Regulation of TGF- β/BMP signalling
SMAD2 Juvenile polyposis TGF- β signal transduction
419
Source: Adapted from(9).
pathways is another key driver of cancer, in which cancer cells exhibit the ability to engage with
apoptotic machinery insufficiently and evade apoptosis(10). In normal function, both intrinsic
and extrinsic apoptosis pathways lead to the activation of cysteine aspartyl- specific proteases or
‘caspases’, which result in cleavage of several proteins, resulting in cell death and completion of the
apoptotic pathway(10). The intrinsic apoptosis pathway is primarily regulated by the fine balance
of the B- cell lymphoma 2 (BCL- 2) family of proteins, classified as either anti- apoptotic or pro-
apoptotic. It is the primary mediator of life and death in cancer cells (11). The upregulation of
anti- apoptotic BCL- 2 proteins (BCL- X
, myeloid cell leukaemia 1 [MCL- 2], BCL- w and A1) and loss
L
of pro- apoptotic genes (BLC- 2 interacting mediator of cell death [BIM], P53- upregulated modula-
tor of apoptosis [PUMA] or truncated BH3 interacting domain death agonist [tBID]) has been
observed in many cancers such as follicular lymphoma, multiple myeloma, breast cancer, prostate
cancer and hepatocellular carcinoma(10, 11).
Death receptors in the extrinsic pathway are part of the tumour necrosis factor (TNF) receptor
gene superfamily (CD95, TRAIL receptors and TNF receptor 1 [TNFR1]) (10). Cancer cells can
impair the signalling of death receptors via the downregulation of receptor surface expression as
part of an adaptive stress response(10). This has been shown to occur in chemotherapy- resistant
leukaemia or neuroblastoma cells due to the downregulation of CD95 expression(12, 13). It has
been demonstrated in colon carcinomas that abnormal transport from intracellular stores to the
cell surface results in resistance to TRAIL- induced cell death (12). In another study assessing
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