Добавил:
Sekretar
kiopkiopkiop18@yandex.ru
t.me/Prokururor I Вовсе не секретарь, но почту проверяю
Опубликованный материал нарушает ваши авторские права? Сообщите нам.
Вуз:
Предмет:
Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5210_Библиотеки_им_академика_М_И_Перельмана
.pdf
27.8 Biomarkers
27.7.2 Oral Lichen Planus
Oral Lichen Planus is a chronic, systemic disease of established immune- mediated pathogenesis(19). Histopathologically, it is characterised by lymphocytic infiltration at the epithelium/connective tissue interface and lymphocytic exocytosis into the basal epithelium with or without saw
tooth elongation of rete ridges(7, 19). Hydropic degeneration of basal epithelial cells and dyskeratotic cells can be seen (7, 19). The appearance of epithelium varies, depending on the clinical
presentation of OLP, ranging from hypertrophic atrophic to erosive and ulcerative forms(7, 19).
Given that 25– 30% of OEDs can also elicit lichenoid inflammation, the distinction between OLP
and OED can, at times, be difficult, and diagnosis of OLP should always be made only in the context of appropriate clinical and histopathological criteria being met(7).
27.7.3 Other Benign Lichenoid Conditions
Other conditions associated with lichenoid inflammation which may need to be considered in the
differential diagnoses of OED include drug reactions, contact lichenoid reaction, graft- versus- host
disease and lupus. Distinction from OED requires a detailed clinical history(7).
27.7.4 Traumatic Ulceration
Cytologic changes accompanying aphthous ulcers or traumatic ulcerative granuloma can also
mimic severe dysplasia(7). However, mixed inflammatory infiltrate, elongation of the rete ridges,
absence of drop- shaped enlargement, absence of paradoxical keratinisation and maintenance of
nuclear polarity rule out OED(7).
459
27.8 Biomarkers
While OED is an essential indicator of the risk of malignant transformation of OPMDs, the histopathologic diagnosis remains subjective, with inter- and intra- observer variations hindering accurate diagnosis and grading. Attention has therefore turned to the search for objective biomarkers
that can be used in the diagnosis and prognostication of OED and OPMDs in general. The biomarkers which have been focused on are largely based on the hallmarks of cancer and on the
principle of the multistage theory of carcinogenesis, whereby cancers develop through progressive
accumulation of specific genetic events, often in a particular sequence, culminating in the transition from normal to dysplastic epithelium to OSCC(17, 20).
The hallmarks of cancer include self- sufficiency in growth signals, insensitivity to antigrowth
signals, avoidance of apoptosis, immortalisation, sustained angiogenesis, invasion and metastasis
and evasion of the host immune system(17, 21, 22). Dysplastic cells are also predisposed to develop
these characteristics as dysplasia progresses to malignancy(17).
27.8.1 Self- sufficiency inGrowth Signals
While normal cells depend on extracellular growth signals to proliferate, cancer cells can grow
without such signals. This can occur through:
1) Over- expression of Extracellular Growth Signals: Over- expression of extracellular growth signals
such as transforming growth factor- alpha (TGF- α), the expression of which has been shown to
increase as OED progresses from low grade to high grade to OSCC(17, 23).
t.me/Dr_Mouayyad_AlbtousH
460
2) Growth Factor Receptor Alterations: Overexpression of certain epidermal growth factor recep-
tors (EGFRs) has been demonstrated to correlate with the severity of dysplasia, including
c- erbB1 (Her1), c- erbB2 (Her2- neu), c- erbB3 (Her3), c- erbB4 (Her4) and Ror2(1,17, 23).
3) Dysregulation of Intracellular Signalling Pathways: In carcinogenesis, direct activation of the
intracellular signalling pathways can occur, enabling cells to proliferate without any exogenous
stimulation(17). Under normal circumstances, the progression of cells through the cell cycle is
tightly regulated by proteins such as cyclin and cyclin- dependent kinase (CDK)(17, 24). These
molecules form a complex resulting in the phosphorylation and inactivation of retinoblastoma
protein (Rb)(17). As a result, a transcription factor E2 promoter- binding factor (E2F) is released,
facilitating the expression of cell cycle control genes, allowing progression through the cell
cycle(17). Dysregulation of expression of these proteins can lead to loss of control of normal
cell growth, resulting in cancer development. With reference to OED:
● Various types of cyclins and CDKs synthesised as the cell progresses through the cycle have
been implicated, namely(17, 23, 24).
→ CDK2: Observed in severe dysplasia and OSCC.
→ CDK4: Found to increase as dysplastic tissue progresses to OSCC.
→ Cyclin A protein: Noted to increase with progression of dysplasia.
→ Cyclin D and E: Demonstrated in OED and OSCC.
● Role of pRb and E2F(17, 23):
→ pRb has been noted to increase with dysplasia progression. In contrast, a significant loss of
pRb has been observed in the transition from hyperplasia to dysplasia.
→ E2F- 1has been shown to increase both oral dysplasia and OSCC.
● Transcription factors(17, 23):
→ The oncoproteins c- fos, c- jun and c- myc have been implicated in developing epithelial
dysplasia.
● Other proliferation markers implicated in OED include Ki- 67, BrdU, silver- binding nucleolar
organiser region (AgNOR), proliferating cell nuclear antigen (PCNA) and minichromosome
maintenance proteins (Mcm 2– 7)(17, 23).
27.8.2 Insensitivity toAntigrowth Signals
Inhibitory signals apply breaks to the cell cycles. Inhibition of these molecules can result in uncontrolled cell proliferation and tumour formation. Biomarkers of importance include:
● P53. One of the most common genetic abnormalities in OSCC involves the gene TP53, with cor-
relations demonstrated between p53 accumulation and histologic grade of dysplasia(17, 23). p63
and p73 are members of the p53 family with higher expression demonstrated in oral cancer and
dysplasia than in normal tissue(17, 23).
● Mouse double minute 2 (MDM2) is an essential regulator of p53 protein, and increased expres-
sion has been observed in OED as it progresses to cancer(17).
● p16 proteins usually block cell cycle progression, and inactivation of the p16 gene facilitates
uncontrolled cell growth. Its expression has been shown to decrease in dysplasia(17, 23).
● Other inhibitors associated with OED include: CDK inhibitors p12, p21, p27, p57 and member
of the F- box family Skp2(17, 23, 24).
27.8.3 Avoidance ofApoptosis
Under normal circumstances, irreparable DNA damage triggers apoptosis, preventing the potentially dangerous propagation of genetically damaged cells(17). Apoptosis controlling molecules
t.me/Dr_Mouayyad_AlbtousH
27.8 Biomarkers
include the pro- apoptotic molecules p53 and Bax, and the anti- apoptotic proteins bcl- 2, mdm2 and
surviving(17). All are dysregulated in dysplasia(17, 23).
DNA damage mismatch repair (MMR) system also appears of significance in OED and
OSCC (25). MMR proteins (MutSα and MutLα) repair DNA base substitution mismatch and
insertion/deletion mismatch, thus playing an essential role in cell cycle arrest and programmed
cell death(25). Any system dysfunction can increase cell survival and cancer risk(25). A significant inverse relationship has been demonstrated between MMR proteins and grades of OED,
highlighting a potential role for such proteins in the risk stratification of OPMDs(25).
Other proteins that regulate apoptosis with a potential role in dysplasia include cyclooxygenases,
cytosolic PLA- 2, heat shock proteins (HSP), metallothionein and P- Akt(17, 23).
27.8.4 Immortalisation
Normal cells cannot divide, eventually reaching a state known as ‘senescence’. Malignant cells can
escape senescence (a process called immortalisation) by lengthening their telomeres (17).
Telomeres consist of arrays of repeated TTAGGG hexamers ranging in length from approximately
5 to 20 kb(23). They are located at the end of chromosomes and function to prevent end- to- end
fusion of chromosomal DNA, thus maintaining the stability of chromosomes(17, 23). With each
cell division, telomeres become shorter, eventually leading to permanent cellular growth cessation
or senescence(17). Immortalisation of cells requires that telomere repeats are maintained at an
amplifiable length(17, 23). Telomeres are synthesised by telomerase, the activity of which often
increases in cancer and can also occur OED(23). Telomerases consist of a catalytic protein subunit,
human telomerase reverse transcriptase (hTERT) and an RNA template (hTR)(17, 23). Enzyme
activity correlates with the level of hTERT expression. Expression of hTERT has been shown to
increase in OED(17, 23).
461
27.8.5 Sustained Angiogenesis
Angiogenesis is one of the vital biologic correlates of malignancy(26). It is essential for tumour
development, progression and metastasis. It is facilitated by increasing expression of pro- angiogenic
factors such as vascular endothelial growth factors (VEGFs), fibroblast growth factors (FGFs) and
heparin- binding protein 17 (HBp17) (17, 23). Pro- angiogenic factors can be produced by the
tumour cells and the inflammatory cells in the associated infiltrates(17, 23).
Upregulation of VEGFs has been noted in OED and hypoxia- inducible factor 1 (HIF- 1) – an
essential regulator of cellular response to hypoxia(17, 23). Expression of FGF- 2 and HBp17was
also observed in dysplasia(17, 23).
27.8.6 Tissue Invasion andMetastasis
Invasion and metastasis is a multistep process involving complex cell- to- cell and cell- to- matrix
interactions. Loss of expression of cell adhesion molecules is an essential event in this process,
and it has been shown that the cadherin/catenin cell adhesion system is often disrupted in
OED(17). Ascatenins are cytoplasmic proteins that bind cadherins to the cytoskeleton, and their
expression was also reduced in dysplasia(17, 23). Expression of numerous other molecules was
also noted to be affected in OED including annexins (calcium and phospholipid- binding proteins involved in the modulation of phospholipase A2, signal transduction, maintenance of
cytoskeleton and extracellular matrix integrity, tissue growth and differentiation); syndecans
(cell- surface molecules that interact with extracellular matrix components, other cell surface
t.me/Dr_Mouayyad_AlbtousH
462
molecules and growth factors); basement membrane components such as collagen IV, collagen
XVII (hemidesmosome component), laminin, integrins (Involved in the maintenance of tissue
integrity and regulation of cell proliferation, growth, differentiation and migration), CD44
(transmembrane glycoproteins), keratins (proteins that constitute the intermediate filament
cytoskeleton of epithelial cells), epithelial cell adhesion molecule (Ep- CAM), perlecan and
matrix metalloproteinases (MMPs)(17, 23, 27).
27.8.7 Evasion ofthe Host Immune System
Regulatory T- cells are essential in controlling the tumour microenvironment by mediating tolerance, suppressing effector T- cells and inhibiting immune- mediated destruction(28). Regulatory T
cells can stimulate dendritic cells to increase PD- L1 expression, leading to immune response evasion by inhibiting T- cell responses(28). The role of PD- 1 and PD- L1 has been investigated in
OPMDs to identify specific biomarkers that can predict progression to malignancy(28). Results
demonstrate expression of PD- 1 and PD- L1 in most OPMD, which appears to correlate with
increased progression(28).
27.9 The Role of MicroRNAs
MiRNAs are small (18– 25 nucleotides) single- stranded non- protein coding RNA molecules that
pair with messenger RNA sites of protein- coding genes to regulate gene expression (29). Each
miRNA can regulate the expression of many genes, and the expression of each target gene may also
be regulated by multiple miRNAs(29, 30). In carcinogenesis, miRNAs can regulate the expression
levels of oncogenes and tumour suppressor genes and may also directly function as oncogenes or
tumour suppressor genes, and altered miRNA expression has been shown to play a role in
OSCC(29, 30).
Studies investigating miRNAs support their potential as prognostic markers for predicting the
malignant transformation of OPMDs(30). To date, 73 uniquely dysregulated miRNAs have been
identified, which may prove helpful in diagnosing and predicting OPMDs(29). Although some
miRNAs can independently differentiate between progressive and non- progressive lesions, it is
generally agreed that utilising panels of multiple miRNAs is the key to optimising their predictive
ability(29, 30).
27.10 Hypoxia inOral Potentially Malignant Disorders
Hypoxia plays a vital role in oral carcinogenesis. During hypoxia, cells exhibit metabolic changes,
increased angiogenic capacity and altered cell growth(26, 31). These cellular responses to hypoxia
are regulated by hypoxia- inducible factors (HIFs)(26).
The HIF pathway regulates tissue responses to hypoxia at the molecular level(26). It facilitates
tumour progression by Kujan etal.(26, 31):
1) Promoting angiogenesis by inducing VEGF
2) Promoting cell survival by upregulation of glucose transporters (Glut- 1 and Glut- 3) and
3) Inducing epithelial- mesenchymal transition (EMT) is regulated by signal transducer and acti-
vator of transcription 3 (STAT3).
t.me/Dr_Mouayyad_AlbtousH
Evidence exists that hypoxia- related changes are involved in the early stages of OSCC development, therefore suggesting a potential role in the malignant transformation of OPMDs (26, 31).
Associations have been described between non- dysplastic epithelial changes, dysplastic lesions
and OSCC and Glut1, HIF- 1α, VEGF and STAT3(26, 31). Thus, the level of hypoxia may assist in
establishing the severity of epithelial changes among OPMDs(26, 31).
In summary, numerous molecular markers relevant to the hallmarks of cancer and playing a role
in the cell cycle have been tested individually and in combinations to develop reliable diagnostic
markers of lesions at high risk of progression to malignancy. However, none of the molecular
markers, singly or combined, are ready for use in routine clinical practice(8).
27.11 Aneuploidy andLoss ofHeterozygosity
Assessments of single biomarkers or biomarker panels are one approach to determining the risk of
malignant transformation of OPMDs. Another approach involves measuring gross chromosomal
changes. This is based on the notion that although mutations and chromosomal rearrangements
accumulate with time in OPMDs and in OSCC, there is little evidence that specific changes are
necessary or sequential(6, 20). Current evidence suggests that genetic changes in OPMD are random or semi- random and not necessarily related to the genetics of OSCC, implying that different
genetic processes may drive dysplasia and carcinoma(6, 20). From this perspective, OPMDs can be
seen as an environment of chromosomal instability in which carcinoma development becomes
more likely than the normal mucosa(6). Thus, OPMDs (and OED) do not represent a stage per se
that progresses to cancer but instead undergo malignant transformation, which can be sudden and
unpredictable(6). According to this view, gross changes in the DNA content or chromosomal complement may serve as better markers of the risk of malignant transformation than assessments of
single biomarkers or biomarker panels(20).
While accurate prediction of malignant transformation of OPMDs is likely to remain challenging, aneuploidy and loss of heterozygosity (LOH) constitute a promising approach (23).
Aneuploidy refers to deviations from the normal diploid nuclear DNA content (20). It can be
assessed by detecting chromosomal amplifications/deletions or measuring total cell DNA content(20). LOH is defined as the loss of one of the alleles of a pair at a constitutional heterozygous
locus and is determined by identifying small DNA sequence changes at specific chromosomal
loci(20). Both indicate significant genetic changes and chromosomal instability and are fundamental to carcinogenesis(23).
Abnormal DNA content has been demonstrated in OPMDs, in clinically normal mucosa affected
by field change and in epithelium adjacent to OSCC (20). However, it is not unique to tissue
exposed to carcinogens and can also develop in tissues as an age- related change(20). Chromosomal
aneuploidy is a change in the chromosomal structure of a cell defined by the deletion or duplication of specific chromosomes(20). In OPMDs, copy number alterations have been demonstrated at
loci on chromosomes 7 and 11, correlating with a risk of malignant transformation(20). DNA aneuploidy refers to a change in individual cells’ total nuclear DNA content without any reference to
which chromosomes are altered(20). DNA ploidy is of value in predicting malignant transformation(32). It has been demonstrated to correlate with the presence and severity of dysplasia, being
more frequent in higher grades of dysplasia and in lesions considered high- risk clinically(20, 23).
In Dysplastic lesions, aneuploidy has also been more frequently demonstrated in high- risk areas,
e.g. the lateral and ventral tongue surfaces and the floor of the mouth(20). A recent meta- analysis
of five studies of pooled OPMDs for the predictive value of DNA aneuploidy reported a 3.12- fold
463
t.me/Dr_Mouayyad_AlbtousH
464
relative risk of malignant transformation for aneuploidy and a 0.18- fold risk for diploidy (33).
Combined with other information (clinical and histopathological), DNA ploidy can further
enhance risk stratification for malignant transformation of OPMDs, thus facilitating the selection
of the most appropriate treatment for the individual patient(20, 33).
Gene conversions, acquired uniparental disomy, deletions, chromosome breakages or loss and
translocations or fusion of two chromosomes are some of the events that result in LOH(20). In
solid cancers, most LOH events result from deletions(20). LOH is significant because it is a common mechanism by which tumour suppressor genes are inactivated(23). In OPMDs, it has been
demonstrated that LOH in regions containing tumour suppressor genes can be an early predictor
of malignant transformation(20). LOH on chromosomes 3p and 9p, 13q and 17p is common in oral
dysplasia. LOH at specific loci has shown some correlation with the histological features of dysplasia(7, 20, 32). As is also the case with DNA ploidy, LOH can predict transformation independent
of dysplasia and LOH at excision margins of OPMD has been associated with an increased risk of
recurrence(7, 20). Thus, adding LOH into a risk stratification model can benefit greatly.
In summary, LOH and DNA aneuploidy in OPMDs signal chromosomal instability, which predisposes to malignant transformation. While, at present, the positive predictive values are not high
enough to dictate treatment choices for individual patients, the negative predictive values are sufficient to identify low- risk patients(20, 33). In several studies, LOH and DNA aneuploidy have
been shown to exceed the predictive value of dysplasia grading and add value to the laboratory
analysis of OPMD samples(20).
27.12 Microbiological Influences andAssociations
27.12.1 Human Papilloma Virus
The reported prevalence of HPV in the oral cavity varies from 0.9 to 12.0%, with that of high- risk
types ranging from 1 to 3%(16). HPV 16 is the most common high- risk type, with HPV 18, −33, −52
and −58 less commonly identified (16, 34– 36). Fortunately, most incident and prevalent HPV
infections are cleared from the oral cavity within one to two years(16). High viral loads increase
the risk of persistent infection(16).
High- risk HPV is a well- established risk factor for oropharyngeal SCC and has also been associated with a subset of OEDs(36). Clinically, such lesions present as leukoplakias, similar to nonHPV- associated lesions (5, 16). Histopathologically, however, HPV- associated OEDs exhibit
characteristic appearance, including parakeratosis, epithelial hyperplasia with thick, deep invading rete ridges and diffuse, full- thickness loss of squamous differentiation(16, 34, 36). Mitotic figures and mitotic- like structures, multinucleated cells and dyskeratotic cells have also been
reported(36). Cytologic indicators of high- risk HPV (predominantly HPV16) in high grade OED
(and strongly associated with p16 expression) include abundance of(7, 35):
1) Karyorrhectic cells, characterised by marked nuclear fragmentation (karyorrhexis) with occa-
sionally enlarged, ‘ballooning’ nuclear degeneration and
2) Apoptotic cells are characterised by hyperchromatic, shrunken nuclei and bright cytoplasmic
eosinophilia.
The floor of the mouth and tongue appear to be the predominant locations for HPV- associated
dysplastic lesions(7, 34– 36). This is most likely the result of the thin, nonkeratinised epithelium
present at those sites(36). Thicker epithelium and keratinisation in other areas of the oral cavity
t.me/Dr_Mouayyad_AlbtousH
may be a barrier and prevent the virus from accessing the basal epithelium to initiate infection(36).
The exact role of HPV in the development of OED remains uncertain, and while these lesions may
progress to HPV- positive oral SCC, how HPV may initiate or influence the progression of OED to
OSCC remains unclear(34, 35).
HPV detection methods include identifying the presence of HPV DNA, the expression of viral
oncoprotein mRNA (i.e. E6 and E7) and p16 overexpression(34, 35). The primary mechanism
of HPV- driven tumorigenesis is based on the expression of viral oncoprotein mRNA and p16
overexpression(35). HPV oncoproteins E6 and E7inactivate tumour suppressor proteins p53
and pRb, with the latter resulting in overexpression of p16(35).
Detection of HPV can vary, depending on the technique used(5, 35). E6/E7 cause HPVdriven tumour growth, and polymerase chain reaction PCR) detection of E6/E7mRNA is the
standard by which other HPV detection techniques are measured(35). This method, however,
cannot be readily performed on formalin- fixed, paraffin- embedded tissue and is technically
challenging(35). The Alternate method involves RNA in situ hybridisation, which can be performed on formalin- fixed, paraffin- embedded tissue and is highly sensitive and specific for
detecting E6/E7mRNA(35). Other methods include immunohistochemistry for p16; although
this method lacks specificity, as in OSCC, nonviral mechanisms can also stimulate p16 overexpression(34, 35). PCR- based techniques, while highly sensitive in identifying HPV DNA and
able to identify large numbers of HPV types, can produce false positive results, as a biologically
relevant infection (i.e. E6/E7 expression) may not necessarily be present(5, 35). The mere presence of HPV DNA in oral samples may indicate transient infection and does not provide evidence of carcinogenicity(34). Finally, in situ hybridisation shows the cellular location of the
HPV DNA and better correlates with oncoprotein expression. Still, it is less sensitive than PCR
and cannot identify all HPV types(35). Thus, in the interest of optimising sensitivity and specificity, the currently recommended approach to HPV testing Involves screening with p16 immunohistochemistry, followed by DNA in situ hybridisation or DNA- based PCR in equivocal
cases(35).
A recent meta- analysis of 832 cases from 31 studies examining HPV DNA prevalence in OED
reported a pooled overall HPV DNA prevalence of 27% and a proportion of HPV16 positivity of 69%
among HPV DNA- positive cases (34). Overexpression of p16 was present in 62% of HPV DNApositive and 18% of HPV DNA- negative cases(34). An Increasing tendency of HPV DNA prevalence with increasing severity of dysplasia was also reported, ranging from 25% in epithelial
dysplasia to 55% in carcinoma in situ(34).
It should be pointed out, however, that this meta- analysis focused on the detection of HPV DNA
in OED by PCR, the mere presence of which does not necessarily translate into transcriptional
HPV activity, and whether it represents transient infection or plays a carcinogenic role remains
unknown(6, 34). Follow- up studies detecting HPV E6/E7mRNA in OED are needed to ascertain
any potential causal associations(34).
The meta- analysis aimed to estimate the carcinogenic activity of HPV in OED by examining the
overexpression of the tumour suppressor protein– p16in relation to HPV status(34). The HPV E7
oncoprotein activates p16, the overexpression of which serves as a marker for HPV- infected oropharyngeal carcinoma(34). However, whether this can be applied to other head and neck cancer
subsites is unknown, as high p16 protein expression can also be caused by mutation or amplification of CDKN2A, RB1mutation or NSD- 1 hypermethylation(34, 35).
As is the case for OED in general, Oral HPV- associated dysplasia can undergo malignant transformation, and the limited data published to date suggest rates comparable to non- HPV- associated
dysplasia (6). How HPV- driven OSCC differs from HPV- associated oropharyngeal carcinoma
465
t.me/Dr_Mouayyad_AlbtousH
466
remains unknown. While improved survival for HPV- positive versus negative oropharyngeal carcinomas has been demonstrated, too few cases of HPV- positive OSCC have been reported to determine if the same holds for the oral cavity(5).
27.12.2 Candida
Numerous environmental risk factors have been associated with the development of OED, including oral mycobiome (oral mycobiota and their collective genomes) (37). The exact mechanisms
remain poorly understood(37).
Fungal organisms constitute part of the human microbiota and, in health, exist harmoniously at
various sites, including the oral cavity(37). Candida is the most common coloniser of the oral
mucosa(37). Immune compromise, local or systemic, leads to dysbiosis and may cause disease(37).
Studies assessing the potential role of oral mycobiota in oral premalignancy show increased yeast
carriage as the epithelium changes from normal to hyperplastic to dysplastic, with the number
of colony- forming units and the presence of Candida hyphae correlating with the severity of
dysplasia(6, 37, 38).
Clinically, candida hyphae within the keratin layers in OPMDs can result in nodular, speckled
and erythematous lesions(6). Reactive changes associated with candida infection can also alter the
appearance of dysplasia, with neutrophil accumulation in the surface layers, cellular atypia, basal
cell hyperplasia and broad rete processes; however, any association between candidosis and carcinogenesis remains theoretical(6). Furthermore, it remains to be determined if treatment of the
candidosis reduces the risk of malignant transformation, although it does improve the lesion’s
clinical appearance and may facilitate diagnosis of OED(6).
The Candida genus, particularly Candida albicans, has been shown to represent an independent
risk factor for oral SCC(38). Aside from increased fungal colonisation in oral cancer patients, the
mycobiome appears to be altered. Within the Candida genus, diversity changes, including an
abundance of uncommon species such as Candida krusei, Candida glabrata and Candida tropicalis, have been observed in patients with dysplastic lesions and oral SCC(37).
While increased fungal burden and dysbiosis have been observed in OPMDs, the underlying
mechanisms that implicate the mycobiome in oral carcinogenesis remain uncertain(10, 37). The
mycobiome may play a role in the initiation of oral carcinogenesis; may facilitate or promote
malignant transformation or represent secondary colonisation of OPMDs(10, 37).
Pathogenic mechanisms through which the mycobiome may initiate oral carcinogenesis include
the secretion of carcinogenic compounds (37). Candida expresses alcohol dehydrogenase, one
involved in ethanol metabolism, to the mutagenic acetaldehyde(3, 38). Compared to healthy controls, Candida was also shown to exhibit increased acetaldehyde production in oral SCC(37).
Increased nitrosamine secretion by fungi has additionally been proposed, with some studies demonstrating an increase in C. albicans strains with prominent nitrosation potential in OPMDs(37).
Shared molecular mechanisms between candida infection and neoplasia have been noted.
Immune responses initiated by IL- 17- secreting cells activated during candidosis correlate with
tumour- promoting inflammatory infiltrates(37). It has also been hypothesised that candidalysin,
an epithelium- damaging toxin expressed by Candida, activates other oncogenic pathways within
the epithelium, including the epidermal growth factor receptor/mitogen- activated protein kinase
axis(3, 37). However, a direct association between candidalysin and oral carcinogenesis has not
been proven.
Notwithstanding the oral mycobiome displaying some oncogenic effects, whether these are
sufficient to initiate dysplasia is yet to be established by high- level evidence(37). It may also be
t.me/Dr_Mouayyad_AlbtousH
hypothesised that while these events may be insufficient to cause epithelial dysplasia per se, they
may act as promoters or facilitators of cancer development. Unfortunately, studies are limited and
definite conclusions cannot be reached(37).
Finally, it remains possible that pathophysiologically, the oral mycobiome and epithelial dysplasia are unrelated and that these two phenomena coexist in the setting of common predisposing
factors(37). Immunocompromise, for example, increases susceptibility to oral candidosis and neoplasia(37). It is also possible that abnormal epithelial architecture predisposes to infections(37).
In the case of passive coexistence, an OPMD may result in passive colonisation by the oral mycobiome, which does not influence its biological behaviour(37).
Despite the characterisation of oral mycobiota in health and disease, the precise role of the mycobiome in the pathogenesis of OPMDs and oral cancer remains elusive(7, 37). It is yet to be determined via high- level evidence whether Candida causes carcinogenesis, acts as a promoting factor,
or is an innocent bystander(37).
Accurate diagnosis of mucosal lesions is essential. Chronic hyperplastic candidosis mimics oral
leukoplakia clinically; however, it resolves with treatment and is not associated with a risk of
malignant transformation(6). Failure of such lesions to resolve after appropriate antifungal treatment warrants further biopsy of the residual lesion to ensure accurate diagnosis(6). Re- biopsy,
however, should be delayed for at least six weeks after treatment, given the turnover time of oral
epithelia (up to three weeks), with additional time needed for inflammation to resolve and normal
epithelial architecture to re- establish(6).
467
27.13 Dysbiosis
Alterations of the oral microbiome have been proposed as a possible risk factor for oral SCC(38)
Porphyromonas gingivalis. Genus Rothia are some of the observed altered microbiome species
associated with oral SCC by promoting inflammation and production of the carcinogenic acetaldehyde(12, 38). Although studied in the context of oral cancer, it remains to be determined what role
(if any) bacterial dysbiosis plays in the development and behaviour of OED.
Reports on microbial diversity and abundance of bacteria in individuals with OED at phyla, family and genus taxonomic levels are limited to date. Studies investigating oral microbiome diversity
in individuals with OED suggest that the diversity of bacterial community groups in individuals
with OED tends to fall between normal and cancer subjects(38). Nonetheless, conclusions regarding cause– effect relationships cannot be drawn, and well- designed prospective cohort studies
are needed.
Although reported microbiota profiles among normal, OED and cancer patients vary between
the studies, compared to controls, a significant increase of phylum Bacteroidetes in subjects with
OED and genus Fusobacterium in both the OED and oral cancer patients appears to be a common
finding(38). Similarly, a reduction of genus Streptococcus has been observed in the OED and SCC
groups compared to normal controls(38).
In the case of Bacteroidetes, Porphyromonas and Prevotella have been noted to increase in
subjects with OED(38). P. gingivalis and Prevotella oulorum have been identified at the species
level(38). These organisms, as well as Fusobacterium, produce volatile sulfur compounds, such
asgenotoxic and mutagenic agent hydrogen sulfide (H
chronic inflammation, cell proliferation, migration, invasion and tumour angiogenesis (38).
P. gingivalis additionally induces the proliferation of epithelial cells through the upregulation of
β- catenin and gingipain- dependent proteolytic degradation, while Fusobacterium nucleatum
S) and methyl mercaptan, which induce
2
t.me/Dr_Mouayyad_AlbtousH
468
(F. nucleatum) through activation of 12kinases(38). P. gingivalis and F. nucleatum also enhanced
signalling along the IL- 6- STAT3 axis, stimulating tumorigenesis by directly interacting with oral
epithelial cells through Toll- like receptors(38). Furthermore, P. gingivalis was also shown to activate the ERK1/2- Ets1, p38/HSP27 and PAR2/NF- kB pathways, stimulating the expression of
proMMP9, which promotes invasion of oral SCC(38). Nonetheless, although multiple oncogenic
effects have been demonstrated, the precise mechanisms by which these periodontal pathogens
could act in cancer progression are unclear.
Diffused carcinogen exposure has been associated with field changes (38). According to this
concept, seemingly normal mucosa may contain significant molecular changes that increase the
risk of cancer development and explain how different parts of the oral cavity remain at risk(38).
Although plausible, whether microbial dysbiosis plays a role in field cancerisation remains to be
determined(38).
27.14 Genetic Disease andImmunosuppression
Several genetic disorders characterised by dysregulation of DNA metabolism have been associated
with OPMDs and OSCC, including:
Dyskeratosis congenita (Zinsser– Cole– Engman syndrome) is a rare hereditary disease attributed to
dysfunctional telomere maintenance(3). Mutations of genes responsible for maintaining telomere structure and function, such as the DKC1 gene encoding the ribonucleoprotein dyskerin,
are believed to be responsible(3). The disease may be X- linked, autosomal dominant or recessive, with variable penetrance(3). Clinically, it is characterised by nail dystrophy, cutaneous
hyperpigmentation, oral leukoplakia, progressive bone marrow failure and a higher incidence of
OSCC (1000 times greater than in non- affected individuals)(39). Leukoplakias develop in childhood and are eventually present in over 80% of individuals affected (39). Unfortunately, the
histopathology of the leukoplakias is rarely reported(39). Early lesions may exhibit no features
of OED, which can develop later(39, 40). Dyskeratosis congenita should always be considered
in young individuals presenting with oral leukoplakia(3). The prognosis is frequently poor due
to OSCC or bone marrow failure(3).
Fanconi anaemia is a rare autosomal recessive disorder of DNA repair genes(3). It is characterised
by skeletal malformations, aplastic anaemia and progressive pancytopenia(3). Fanconi anaemia
may culminate in bone marrow failure, leukaemia and solid tumours, including head and neck
cancers (650- fold risk increase), with oral squamous cell carcinoma being the most common and
of early onset(3, 39). Individuals with Fanconi anaemia are also known to present with OPMDs,
particularly with oral leukoplakia(3). Oral leukoplakia has been reported in up to 12% of children
before hematopoietic stem cell transplantation, which does not eliminate the risk of OSCC(39).
Xeroderma pigmentosum is a rare autosomal recessive disorder of nucleotide excision repair, asso-
ciated with an increased risk of carcinomas of the sun- exposed skin and lips(9, 39). Gingival
and tongue SCCs have also been reported, presumably preceded by OED, suggesting that factors
other than sunlight may contribute to the carcinogenesis of this disorder(39).
Oral epidermolysis bullosa (some forms only) is a disorder typified by severe epidermal fragility
associated with trauma- induced blistering, progressive soft tissue scarring and increased risk of
skin cancer(3, 9).
Plummer– Vinson syndrome (Paterson– Kelly syndrome) is characterised by post- cricoid oesophageal
webs, atrophic glossitis, koilonychia, dysphagia and increased risk of upper digestive tract
t.me/Dr_Mouayyad_AlbtousH
Соседние файлы в папке Библиотека им академика М.И. Перельмана